EP0210156B1 - Molecular complexes formed from a benzofurane derivative and aluminium chloride, their preparation and their use - Google Patents
Molecular complexes formed from a benzofurane derivative and aluminium chloride, their preparation and their use Download PDFInfo
- Publication number
- EP0210156B1 EP0210156B1 EP86870090A EP86870090A EP0210156B1 EP 0210156 B1 EP0210156 B1 EP 0210156B1 EP 86870090 A EP86870090 A EP 86870090A EP 86870090 A EP86870090 A EP 86870090A EP 0210156 B1 EP0210156 B1 EP 0210156B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- benzofuran
- benzoyl
- alkyl
- toluene
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 title claims description 167
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 294
- 238000010992 reflux Methods 0.000 claims description 40
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- -1 4-methoxy benzoyl halide Chemical class 0.000 claims description 22
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 17
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000001907 coumarones Chemical class 0.000 abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- REXJJQDLLTVPDO-UHFFFAOYSA-N C(CCC)C1=C(OC2=C1C=CC=C2)C(C1=CC=C(C=C1)OC)=O Chemical compound C(CCC)C1=C(OC2=C1C=CC=C2)C(C1=CC=C(C=C1)OC)=O REXJJQDLLTVPDO-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 16
- 239000008367 deionised water Substances 0.000 description 14
- 229910021641 deionized water Inorganic materials 0.000 description 14
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- CJCYOROSBGBHSU-UHFFFAOYSA-N (3-butyl-1-benzofuran-2-yl)-(4-hydroxyphenyl)methanone Chemical compound C(CCC)C1=C(OC2=C1C=CC=C2)C(C1=CC=C(C=C1)O)=O CJCYOROSBGBHSU-UHFFFAOYSA-N 0.000 description 10
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- YKTKSGMDYIJVFC-UHFFFAOYSA-N (3-ethyl-1-benzofuran-2-yl)-(4-hydroxyphenyl)methanone Chemical compound O1C2=CC=CC=C2C(CC)=C1C(=O)C1=CC=C(O)C=C1 YKTKSGMDYIJVFC-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RKAPEFZCHGKELD-UHFFFAOYSA-N C(C)C1=C(OC2=C1C=CC=C2)C(C1=CC=C(C=C1)OC)=O Chemical compound C(C)C1=C(OC2=C1C=CC=C2)C(C1=CC=C(C=C1)OC)=O RKAPEFZCHGKELD-UHFFFAOYSA-N 0.000 description 8
- 229960005260 amiodarone Drugs 0.000 description 8
- 229960003545 benzarone Drugs 0.000 description 8
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 8
- 238000010520 demethylation reaction Methods 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000012429 reaction media Substances 0.000 description 8
- NBZQDHFJJVOLEP-UHFFFAOYSA-N 1-benzofuran-2-yl-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC2=CC=CC=C2O1 NBZQDHFJJVOLEP-UHFFFAOYSA-N 0.000 description 7
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 229960002529 benzbromarone Drugs 0.000 description 7
- CZCHIEJNWPNBDE-UHFFFAOYSA-N benziodarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(O)C(I)=C1 CZCHIEJNWPNBDE-UHFFFAOYSA-N 0.000 description 7
- 229960004411 benziodarone Drugs 0.000 description 7
- 230000017858 demethylation Effects 0.000 description 7
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 7
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 5
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 238000004061 bleaching Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000004611 spectroscopical analysis Methods 0.000 description 4
- MFJCKQFUMBQBDU-UHFFFAOYSA-N 1-benzofuran-2-yl-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC2=CC=CC=C2O1 MFJCKQFUMBQBDU-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 125000001033 ether group Chemical group 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- TTXQKBMNVDJBPZ-UHFFFAOYSA-N (2-ethyl-1-benzofuran-3-yl)-(4-methoxyphenyl)methanone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(OC)C=C1 TTXQKBMNVDJBPZ-UHFFFAOYSA-N 0.000 description 2
- UHCUQSBAYHCKGQ-UHFFFAOYSA-N (3-butyl-1-benzofuran-2-yl)-(4-hydroxy-3,5-diiodophenyl)methanone Chemical compound C(CCC)C1=C(OC2=C1C=CC=C2)C(C1=CC(=C(C(=C1)I)O)I)=O UHCUQSBAYHCKGQ-UHFFFAOYSA-N 0.000 description 2
- OVJKFJDEVKABNF-UHFFFAOYSA-N 2-butyl-1-benzofuran Chemical compound C1=CC=C2OC(CCCC)=CC2=C1 OVJKFJDEVKABNF-UHFFFAOYSA-N 0.000 description 2
- RAGSWDIQBBZLLL-UHFFFAOYSA-N 2-chloroethyl(diethyl)azanium;chloride Chemical compound Cl.CCN(CC)CCCl RAGSWDIQBBZLLL-UHFFFAOYSA-N 0.000 description 2
- KJHYAEZMOHLVCH-UHFFFAOYSA-N 2-ethyl-1-benzofuran Chemical compound C1=CC=C2OC(CC)=CC2=C1 KJHYAEZMOHLVCH-UHFFFAOYSA-N 0.000 description 2
- AVVBGNGFVUYOGL-UHFFFAOYSA-N 4-(2-benzofuran-1-yl)phenol Chemical compound OC1=CC=C(C=C1)C=1OC=C2C1C=CC=C2 AVVBGNGFVUYOGL-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- WETAMBWKDPBAHK-UHFFFAOYSA-N C1C=C2C(=CC=CC2(C(=O)C3=CC=CC=C3)O)O1 Chemical compound C1C=C2C(=CC=CC2(C(=O)C3=CC=CC=C3)O)O1 WETAMBWKDPBAHK-UHFFFAOYSA-N 0.000 description 2
- YKBLKFJTGZPTFU-UHFFFAOYSA-N COC1=CC=C(C=C1)C(=O)C2=C3C=CC=C3C=CO2 Chemical compound COC1=CC=C(C=C1)C(=O)C2=C3C=CC=C3C=CO2 YKBLKFJTGZPTFU-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000020176 deacylation Effects 0.000 description 2
- 238000005947 deacylation reaction Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- KKNBHCBBPUMKCY-UHFFFAOYSA-N (2-hydroxy-1-benzofuran-4-yl)-phenylmethanone Chemical compound OC1=CC2=C(O1)C=CC=C2C(C2=CC=CC=C2)=O KKNBHCBBPUMKCY-UHFFFAOYSA-N 0.000 description 1
- XEPIGVOWGIZGPU-UHFFFAOYSA-N (3-ethyl-1-benzofuran-2-yl)-(4-hydroxy-3,5-diiodophenyl)methanone Chemical compound C(C)C1=C(OC2=C1C=CC=C2)C(C1=CC(=C(C(=C1)I)O)I)=O XEPIGVOWGIZGPU-UHFFFAOYSA-N 0.000 description 1
- 0 *c1ccc(C=C)cc1 Chemical compound *c1ccc(C=C)cc1 0.000 description 1
- TWWAVGXQPVEBKZ-UHFFFAOYSA-N 1-benzofuran-3-yl(phenyl)methanone Chemical class C=1OC2=CC=CC=C2C=1C(=O)C1=CC=CC=C1 TWWAVGXQPVEBKZ-UHFFFAOYSA-N 0.000 description 1
- WPWHSFAFEBZWBB-UHFFFAOYSA-N 1-butyl radical Chemical compound [CH2]CCC WPWHSFAFEBZWBB-UHFFFAOYSA-N 0.000 description 1
- VXXUFVQJZRTWBU-UHFFFAOYSA-N 1-butyl-2-benzofuran Chemical compound C1=CC=CC2=C(CCCC)OC=C21 VXXUFVQJZRTWBU-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- OUTOYQZBWUUTFG-UHFFFAOYSA-N C(C)C1=C(OC2=C1C(=CC=C2)C(C2=CC=CC=C2)=O)O Chemical compound C(C)C1=C(OC2=C1C(=CC=C2)C(C2=CC=CC=C2)=O)O OUTOYQZBWUUTFG-UHFFFAOYSA-N 0.000 description 1
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- PSYQIKJOCMPLCX-UHFFFAOYSA-N CC(CC=C1)c2c1[o]pp2 Chemical compound CC(CC=C1)c2c1[o]pp2 PSYQIKJOCMPLCX-UHFFFAOYSA-N 0.000 description 1
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- UBAHTUBOJQHNOH-UHFFFAOYSA-N N/[O]=N\c(cc1)ccc1OC=N Chemical compound N/[O]=N\c(cc1)ccc1OC=N UBAHTUBOJQHNOH-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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- 230000003416 augmentation Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
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- 229910052742 iron Inorganic materials 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
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- 230000002441 reversible effect Effects 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/06—Aluminium compounds
- C07F5/069—Aluminium compounds without C-aluminium linkages
Definitions
- the present invention relates, in general, to new molecular complexes formed from a derivative of benzofuran and aluminum chloride, to their preparation and to their use.
- the molecular complexes of the invention correspond to the general formula: in which R represents an alkyl radical and R represents one of the radicals:
- alkyl radical is meant, in the present context, a hydrocarbon radical, linear or branched having from 1 to 4 carbon atoms more especially an ethyl or n-butyl radical.
- the complexes of formula 1 can be widely used as synthesis intermediates, in particular for the final synthesis of benzofuran derivatives described in French patents Nos. 1,260,578 and 1,339,389.
- Such derivatives are in particular benzarone or ethyl-2 (4-hydroxy-benzoyl) -3 benzofuran, benziodarone or ethyl-2 (3,5-diiodo-4-hydroxy-benzoyl) -3 benzofuran, benzbromarone or 2-ethyl (3,5-dibromo-4 hydroxy-benzoyl) -3 benzofuran or amiodarone or 2-n-butyl (3,5-diiodo-3,5 p-diethytaminoethoxy-benzoyl) -3 benzofuran.
- Benzarone has therefore been shown to be useful for its phlebotonic effect and for curbing capillaroveinous inflammatory reactions, benziodarone for its coronarodilator and hypouricemiant action, benzbromarone for its hypouricemiant effect and amiodarone for its antianginal and antiarrhythmic properties.
- a first subject of the invention therefore relates to the molecular complexes of formula as new industrial products useful in particular as intermediates for example for the final synthesis of benzarone, benziodarone, benzbromarone and amiodarone.
- Lewis bases such as ketones, ethers, amides can form molecular complexes with Lewis acids such as titanium, iron or aluminum chloride.
- composition of these complexes is variable depending on the conditions of production and the base / acid molar ratios.
- anhydrous aluminum chloride is completely insoluble in aromatic hydrocarbons such as benzene or toluene.
- this product dissolves at a temperature less than or equal to 40 ° C. practically instantaneously in toluene or benzene solutions of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran .
- the 1: 1 complex thus defined could be isolated from chloromethylenic solutions.
- Another subject of the invention relates to a process for the preparation of 1: 1 molecular complexes of formula in which R represents the radical process according to which aluminum chloride and 2-alkyl (4-methoxy-benzoyl) -3-benzofuran are reacted in the ratio 1 to 2: 1, in an aromatic hydrocarbon medium such as for example toluene or benzene or in a chloroalkane medium such as dichloromethane and at a temperature less than or equal to room temperature to obtain the aluminum chloride / 2-alkyl (4-methoxybenzoyl) -3 benzofuran 1: 1 complex.
- R represents the radical process according to which aluminum chloride and 2-alkyl (4-methoxy-benzoyl) -3-benzofuran are reacted in the ratio 1 to 2: 1, in an aromatic hydrocarbon medium such as for example toluene or benzene or in a chloroalkane medium such as dichloromethane and at a temperature less than or equal to room temperature to
- the invention relates to a process for the preparation of 2: 1 molecular complexes of formula 1 in which R represents the radical process by which a solution containing the 1: 1 complex according to the invention is brought to reflux, that is to say a solution formed from 1 to 2 moles of aluminum chloride per mole of 2-alkyl (methoxy -4 benzoyl) -3 benzofuran and an aromatic hydrocarbon such as benzene or toluene as solvent, to obtain the aluminum chloride / 2-alkyl (4-hydroxybenzoyl) -3 benzofuran 2: 1 complex.
- R represents the radical process by which a solution containing the 1: 1 complex according to the invention is brought to reflux, that is to say a solution formed from 1 to 2 moles of aluminum chloride per mole of 2-alkyl (methoxy -4 benzoyl) -3 benzofuran and an aromatic hydrocarbon such as benzene or toluene as solvent, to obtain the aluminum chloride / 2-alkyl (4-hydroxybenzo
- a solution of 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3-benzofuran is produced at a temperature less than or equal to room temperature. aromatic hydrocarbon. Then poured into an aromatic hydrocarbon brought to reflux, the solution thus obtained which contains the aluminum chloride / alkyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex according to the invention so as to form the complex aluminum chloride / 2-alkyl (4-hydroxy benzoyl) -3 benzofuran 2: 1 according to the invention.
- the invention also relates to a solution containing the molecular complexes of the invention and particularly suitable as a reaction medium for causing the demethylation of the ether group of a 2-alkyl (4-methoxy-benzoyl) -3 benzofuran, solution formed from 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran and of an aromatic hydrocarbon such as benzene or toluene as solvent.
- This solution contains the 1: 1 complex according to the invention and at reflux temperature, the 2: 1 complex of the invention.
- the starting alkyl-2 (4-methoxy benzoyl) -3 benzofurans are known products which can be prepared, for example, according to the process described in Bull. Soc. Chim. France pp. 685-688 (1960) or in French Patent No. 1,260,578, by condensation, according to the Friedel-Crafts reaction, of a 2-alkyl benzofuran and 4-methoxy-benzoyl chloride in benzene, at a temperature between 0 ° C and room temperature, and in the presence of stannic chloride as catalyst followed by hydrolysis in the presence of a strong acid such as hydrochloric acid.
- 2-alkyl (4-methoxy benzoyl) -3 benzofuran is prepared at a temperature between -10 ° C. and room temperature also according to the Friedel-Crafts reaction from 2-alkyl.
- ferric chloride is used as catalyst.
- ferric chloride appears, in the present case, more selective than stannic chloride while providing practically quantitative yields.
- the 2: 1 molecular complexes of the invention can be used for the preparation of 2-alkyl (4-hydroxy-benzoyl) -3 benzofuran.
- This variant has the drawback of maintaining, in the reaction medium, a very large excess of aluminum chloride relative to the benzofuran derivative throughout the duration of the casting, which can lead to partial deacylation of the 2-alkyl. (4-methoxy benzoyl) -3 benzofuran.
- a solution of 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran in l is formed at a temperature lower than or equal to room temperature.
- aromatic hydrocarbon chosen so as to form the alumimium chloride / 2-alkyl (4-methoxy benzoyl) -3 benzofuran 1: 1 complex of the invention and the solution obtained is poured in, for example a solution at approximately 30% of this complex in the solvent in question maintained at reflux, which causes the formation of the aluminum chloride / 2-alkyl (4-hydroxy benzoyl) -3 benzofuran 2: 1 complex of the invention.
- the hydrolysis of the 2: 1 complex solution thus formed is then carried out as indicated above, that is to say in the presence of a strong acid at a temperature not exceeding 75 ° C. to 80 ° C.
- this compound is heated to 210-220 ° C in the presence of pyridine hydrochloride and hydrolyzed in the presence of hydrochloric acid such as described in French Patent No. 1,260,578.
- the 2-alkyl (4-hydroxy benzoyl) -3 benzofurans can themselves be used as synthesis intermediates to prepare in particular benziodarone, benzbromarone or amiodarone according to known methods.
- benziodarone and benzbromarone can be obtained respectively by iodination or bromination of 2-ethyl (4-hydroxy-benzoyl) -3 benzofuran by means of iodine or bromine respectively in homogeneous phase and in the presence of a solution alkali metal acetate / acetic acid buffer and amiodarone can be prepared by iodination of n-butyl-2 (4-hydroxy benzoyl) -3 benzofuran, in a similar manner to that described above, to obtain n-butyl-2 ( 3,5-diiodo-4-hydroxy-benzoyl) -3 benzofuran followed by etherification with 1-diethylamino-2-chloroethane hydrochloride in the presence of an alkali metal carbonate / alkali metal bicarbonate buffer solution.
- the honey obtained does not crystallize in the freezer after 3 p.m. at -20 ° C. It is taken up twice with 50 ml of carbon tetrachloride and a second crystallization is observed after 48 h at -20 ° C.
- the crystals are isolated and dried under a stream of dry nitrogen at -20 ° C. and they are stored in the freezer.
- the reaction medium is gradually cooled.
- the crystallization begins around + 40 ° C. It is then wrung after 2 hours of holding at + 5 ° C and the spin cake is dried in a vacuum oven at + 55 ° C under a stream of dry nitrogen.
- reaction medium is maintained at -10 ° ⁇ 2 ° C for 15 min. then allowed to spontaneously return to room temperature. Maintained for 6 hours with stirring and ice again around 0 ° C. 200 g of purified water are then gradually introduced without exceeding 20 ° C.
- the insoluble material is filtered (4-methoxy benzoic acid) and then rinsed on the filter with 90 g of toluene.
- the filtrates are combined in the funnel, the lower aqueous phase is decanted and the organic layer is washed with a solution of 30 g of 36% hydrochloric acid in 200 g of purified water and then with water until neutral.
- the organic phase is dried and the solvent is removed in vacuo up to a temperature of 80 ° C. in the mass under residual pressure of approximately 50 mm Hg.
- n-butyl-2 (4-methoxy benzoyl) -3 benzofuran obtained according to this method leads on average to the following contents of known impurities by thin layer chromatography.
- 174 g (1 mole) of 2-n-butyl benzofuran and 520 g of toluene are introduced into a reactor fitted with stirring devices, introduction of reagents and a condenser. Traces of water are caused by azeotropic distillation.
- the mixture is cooled to 20 ° C and rapidly added 174 g (1.02 mole) of 4-methoxy benzoyl chloride. After cooling to -10 ° C, the medium is treated with 130 g of ferric chloride added at once. After 15 min. at this temperature, the mixture is allowed to return to ambient temperature and is maintained there for 6 h with stirring. It is hydrolyzed by the addition of 200 ml of water while not allowing the temperature to exceed 20 ° C. After 15 min.
- an insoluble material (4-methoxy benzoic acid) is filtered, the filter is washed with toluene and the aqueous phase is separated.
- the organic phase is washed with a solution of 30 g of 36% hydrochloric acid in 200 ml of water then with water until neutral and then dried.
- a toluene solution is thus obtained containing approximately 308 g (approximately 100%) of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran which is used as it is.
- a toluene solution of 308.3 g of crude n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran (expressed as dry extract: 1 mol) as obtained in paragraph a) above is introduced into a reactor. , that is to say a solution at about 30%.
- a toluene solution is thus obtained containing the aluminum chloride / n-butyl-2 (4-methoxybenzoyl) -3 benzofuran 1: 1 complex.
- 253 g of anhydrous toluene are introduced into a second perfectly dry reactor and then, under cooling, 241 g (1.8 mole) of anhydrous aluminum chloride.
- Om brings the mass temperature to 0 ⁇ 5 ° G and the toluene solution of ethyl-2 (4-methoxy benzoyl) -3 benzofuran prepared in the first reactor is added. The addition is done in 90 min. approximately under external cooling so as not to exceed 15 ° C.
- the solution containing the aluminum chloride / ethyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex thus formed is then kept at a temperature less than or equal to 15 ° C.
- 356 g of anhydrous toluene are introduced into the first reactor and then the mixture is stirred and under a residual pressure of 300 - 350 mm Hg before bringing the toluene to reflux (mass temperature: 84 ⁇ 1 ° C).
- the vacuum and the temperature are stabilized, the installation is distilled and then the solution of the second reactor containing the complex is introduced regularly (total time of introduction of the complex: 4 to 5 h; toluene distillation: approximately 1400 g ).
- the second reactor is rinsed with 48 g of anhydrous toluene and the mass is brought to 100 ° C. while gradually reducing the vacuum in the reactor (toluene distillation: approximately 105 g) which causes the formation of aluminum chloride / ethyl- complex.
- the organic phase is washed at 40 ⁇ 2 ° C for 30 min. with a solution, previously prepared, of 150 g of deionized water and 225 g of 36% hydrochloric acid. Decanted and always washed at 40 ° C, with 3 to 5 fractions of 200 g of deionized water until pH > 5 of the effluent.
- the toluene solution is treated with 45 g of activated carbon.
- the mixture is brought to reflux and the water is removed by azeotropy. It is filtered hot to remove impurities, always rinsed hot with 68 g of toluene and the filtrates are combined.
- a toluene solution is thus obtained containing approximately 190 g (approximately: 90%) of ethyl-2 (4-methoxy benzoyl) -3 benzofuran which is used as it is.
- a toluene solution of 280.3 g of ethyl-2 (4-methoxy-benzoyl) -3 benzofuran (expressed as dry extract - 1 mole) as introduced in paragraph a) is introduced. , that is to say a solution at about 30%. It is cooled to a temperature less than or equal to 5 ° C. and, with stirring, 266 g (2 moles) of anhydrous aluminum chloride are added quickly and at once to form a solution containing the aluminum chloride / ethyl-2 complex.
- (4-methoxy benzoyl) -3 benzofuran 1 1. This solution containing the complex is kept under stirring for 30 min. at temperatures below 30 ° C and away from humidity.
- the toluene solution of molecular complex obtained in Example 3b is poured, with stirring, cooled to 75 ° C. After 15 min, the aqueous phase is separated and the organic phase is washed until neutral with water. The toluene phase is dried by azeotropic distillation of water (distillation of 92 g of toluene) and it is discolored by treatment at 80 ° C. with bleaching earth. After filtration and rinsing of the filter with toluene, the filtrate is cooled to -5 ° to -10 ° C and the desired product is isolated by wringing.
- the toluene solution of molecular complex obtained in Example 5b
- the toluene solution of molecular complex is added within 1 to 2 hours and without exceeding 80 ° C. , previously cooled to 75 ° C.
- the aqueous phase is decanted below 75-80 ° C and the organic layer is washed at this temperature with 3 fractions each of 280 g of deionized water.
- the medium is dried by azeotropy at normal pressure via a Dean-Stark system until a head temperature of 108-110 ° C is obtained. Cool to 80 ° C and treat for 15 min. with 11 g of bleaching earth.
- the toluene solution of molecular complex, obtained in Example 6b), previously cooled to 70 ⁇ 5 ° C, is introduced into 600 g of deionized water.
- the mixture is again brought to reflux quickly and then cooled to 70 ⁇ 5 ° C. in order to decant the lower aqueous layer.
- the organic layer is always washed at 70 + 5 ° C. with a solution of 42 g of 36% hydrochloric acid in 266 g of deionized water and then until neutral with 4 fractions each of 266 g of deionized water.
- the organic layer is dried by azeotropy at normal pressure (toluene / water distillate: approximately 244 g or 280 ml) and the medium obtained is treated with 84 g of bleaching earth for 15 min. at 80 ° C. It is filtered, rinsed hot with 56 g (65 ml) of toluene and the filtrates are combined. Crystallized by cooling and filtered after 2 h at -5 to -10 ° C. Rinsed with 168 g (195 ml) of ice-cold toluene and dried to constant weight in a ventilated oven at 60 ° C.
- the toluene solution of molecular complex obtained in Example 7, previously cooled to 80 ⁇ 5 ° C. is introduced into 600 g of deionized water.
- the mixture is again brought to reflux quickly, then cooled to 70 ⁇ 5 ° C. in order to decant the lower aqueous layer.
- the organic layer is always washed at 70 ⁇ 5 ° C with a solution of 42 g of 36% hydrochloric acid in 266 g of deionized water and then until neutral with 4 fractions each of 266 g of deionized water.
- the organic layer is dried by azeotropy at normal pressure (toluene / water distillate: approximately 244 g or 280 ml) and the medium obtained is treated with 84 g of bleaching earth for 15 min. at 80 ° C. It is filtered, rinsed hot with 56 g (65 ml) of toluene and the filtrates are combined. Crystallized by cooling and filtered after 2 h at -5 to -10 ° C. Rinse with 168 g (195 ml) of ice-cold toluene and dry to constant weight in a ventilated oven at 60 ° C.
- the toluene solution of molecular complex obtained in Example 4b) is hydrolyzed by addition of a solution of 46.2 g of 36% hydrochloric acid in 600 g of 'distilled water.
- the apparatus is rinsed with 123 g of toluene which is then added to the hydrolysis medium.
- the organic layer is decanted and washed, at 70 ° C. with fractions of 308 g of purified water until neutral.
- the organic layer is dried by azeotropy while distilling about 92 g of toluene.
- the medium is treated at 80 ° C. with 12.3 g of bleaching earth, filtered and rinsed with 92 g of hot toluene.
- the filtrates are combined, cooled to 35 ° C. and waits for crystallization to be well initiated before icing at -5 to -10 ° C. Maintained for 2 hours at this temperature, wring, rinse with 200 g of ice-cold toluene and dry to constant weight in a ventilated oven at 60 ° C.
- the mixture is brought to reflux for 10 min. (mass temperature: 84 ° C - release of sulfuric anhydride) and the lower aqueous phase is decanted.
- the toluene layer is washed at 75 to 80 ° C successively with 400 g of purified water, 100 g of an aqueous solution of sodium bisulfite and 2 fractions each of 400 g of purified water. Decant as much as possible after the last wash and treat with 22 g of activated carbon for 30 min. at reflux. Filtered while hot, rinsed with 380 g of hot toluene and the filtrates are combined.
- the aqueous saline layer is decanted at 75 ⁇ 5 ° C and the toluene layer is washed, at this temperature with 4 fractions each of 800 g of purified water.
- the toluene solution is treated with 20.5 g of activated carbon, filtered, rinsed with approximately 220 g of toluene and the filtrates are combined.
- the truly acidic pH is checked at the end of introduction and after 30 min. contact at 70 ⁇ 5 ° C.
- the water pump is gradually put under vacuum and about 400 ml of toluene / water / hydrochloric acid are distilled (end of distillation: residual pressure ⁇ 150 mm; mass temperature ⁇ 75 ° C). It is crystallized with slow stirring with a water bath for about 8 hours and is filtered at 10 to 15 ° C. Rinsed with 4 fractions each of 180 ml of filtered toluene and dried to constant weight in a ventilated oven at 60 ° C.
- n-butyl-2 hydrochloride (3,5-diiodo-3,5 ⁇ -diethylaminoethoxy-benzoyl) -3 benzofuran or amiodarone hydrochloride are thus obtained.
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Abstract
Description
La présente invention se rapporte, d'une manière générale, à de nouveaux complexes moléculaires formés d'un dérivé de benzofuranne et de chlorure d'aluminium, à leur préparation ainsi qu'à leur utilisation.The present invention relates, in general, to new molecular complexes formed from a derivative of benzofuran and aluminum chloride, to their preparation and to their use.
Les complexes moléculaires de l'invention répondent à la formule générale:
Par radical "alkyle", on désigne, dans le présent contexte, un radical hydrocarboné, linéaire ou ramifié ayant de 1 à 4 atomes de carbone plus spécialement un radical éthyle ou n-butyle.By "alkyl" radical is meant, in the present context, a hydrocarbon radical, linear or branched having from 1 to 4 carbon atoms more especially an ethyl or n-butyl radical.
Les complexes de formule 1 peuvent être largement utilisés comme intermédiaires de synthèse, notamment pour la synthèse finale de dérivés de benzofuranne décrits dans les brevets français Nos. 1 260 578 et 1 339 389. De tels dérivés sont notamment la benzarone ou éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne, la benziodarone ou éthyl-2(diiodo-3,5 hydroxy-4 benzoyl)-3 benzofuranne, la benzbromarone ou éthyl-2 (dibromo-3,5 hydroxy-4 benzoyl)-3 benzofuranne ou l'amiodarone ou n-butyl-2(diiodo-3,5 p-diéthytaminoéthoxy-4 benzoyl)-3 benzofuranne.The complexes of formula 1 can be widely used as synthesis intermediates, in particular for the final synthesis of benzofuran derivatives described in French patents Nos. 1,260,578 and 1,339,389. Such derivatives are in particular benzarone or ethyl-2 (4-hydroxy-benzoyl) -3 benzofuran, benziodarone or ethyl-2 (3,5-diiodo-4-hydroxy-benzoyl) -3 benzofuran, benzbromarone or 2-ethyl (3,5-dibromo-4 hydroxy-benzoyl) -3 benzofuran or amiodarone or 2-n-butyl (3,5-diiodo-3,5 p-diethytaminoethoxy-benzoyl) -3 benzofuran.
Ces composés se sont révélés particulièrement intéressants pour leurs applications thérapeutiques. Ainsi, la benzarone s'est montrée utile par son effet phlébotonique et freinateur des réactions inflammatoires capillaroveineuses, la benziodarone, par son action coronarodilatatrice et hypouricémiante, la benzbromarone par son effet hypouricémiant et l'amiodarone par ses propriétés antiangineuses et antiarythmiques cardiaques.These compounds have proved to be particularly advantageous for their therapeutic applications. Benzarone has therefore been shown to be useful for its phlebotonic effect and for curbing capillaroveinous inflammatory reactions, benziodarone for its coronarodilator and hypouricemiant action, benzbromarone for its hypouricemiant effect and amiodarone for its antianginal and antiarrhythmic properties.
Un premier objet de l'invention se rapporte en conséquence aux complexes moléculaires de formule en tant que produits industriels nouveaux utiles notamment comme intermédiaires par exemple pour la synthèse finale de la benzarone, la benziodarone, la benzbromarone et l'amiodarone.A first subject of the invention therefore relates to the molecular complexes of formula as new industrial products useful in particular as intermediates for example for the final synthesis of benzarone, benziodarone, benzbromarone and amiodarone.
Il est connu que les bases de Lewis telles que les cétones, les éthers, les amides peuvent former des complexes moléculaires avec des acides de Lewis tels que le chlorure de titane, de fer ou d'aluminium.It is known that Lewis bases such as ketones, ethers, amides can form molecular complexes with Lewis acids such as titanium, iron or aluminum chloride.
Des complexes plus ou moins stables, par exemple de type
- FIGOO/10
ont parfois été isolés et étudiés à l'état solide malgré leur instabilité et hygroscopicité importantes.More or less stable complexes, for example of the type
- FIGOO / 10
have sometimes been isolated and studied in the solid state despite their considerable instability and hygroscopicity.
La composition de ces complexes est variable selon les conditions d'obtention et les rapports molaires base/acide.The composition of these complexes is variable depending on the conditions of production and the base / acid molar ratios.
Des exemples de tels complexes entre la benzophénone ou l'acétophénone d'une part et le chlorure d'aluminium d'autre part ont été décrits dans Helv. Chim. Acta, 1954, Vol. XXXVII, IV, 147,1273 et 1958, Vol. XLI V, 146, 1333. Cependant, aucun complexe moléculaire dérivé de benzofuranne/acide de Lewis en particulier chlorure d'aluminium n'a été rapporté jusqu'à présent.Examples of such complexes between benzophenone or acetophenone on the one hand and aluminum chloride on the other hand have been described in Helv. Chim. Acta, 1954, Vol. XXXVII, IV, 147,1273 and 1958, Vol. XLI V, 146, 1333. However, no molecular complex derived from benzofuran / Lewis acid, in particular aluminum chloride, has been reported so far.
En outre, on sait que le chlorure d'aluminium anhydre est totalement insoluble dans les hydrocarbures aromatiques tels que le benzène ou le toluène.In addition, it is known that anhydrous aluminum chloride is completely insoluble in aromatic hydrocarbons such as benzene or toluene.
Or, on a pu remarquer dans le cadre de la présente invention, que ce produit se solubilise à température inférieure ou égale à 40°C pratiquement instantanément dans des solutions toluéniques ou benzéniques d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.Now, it has been noted in the context of the present invention, that this product dissolves at a temperature less than or equal to 40 ° C. practically instantaneously in toluene or benzene solutions of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran .
Cette "dissolution" s'accompagne d'une forte exothermicité et peut s'observer pour des rapports molaires chlorure d'aluminium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne allant jusqu'à 2,6.This "dissolution" is accompanied by strong exothermicity and can be observed for molar ratios of aluminum chloride / 2-alkyl (4-methoxy benzoyl) -3 benzofuran of up to 2.6.
On a alors émis l'hypothèse que cette dissolution du chlorure d'aluminium dans de telles solutions d'hydrocarbure aromatique pourrait provenir de la formation d'un ou de plusieurs complexes moléculaires entre le chlorure d'aluminium et l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.It was then hypothesized that this dissolution of aluminum chloride in such aromatic hydrocarbon solutions could result from the formation of one or more molecular complexes between aluminum chloride and 2-alkyl (methoxy -4 benzoyl) -3 benzofuran.
En conséquence, on a entrepris des études spectrales de manière à vérifier cette hypothèse et définir l'interaction supposée entre l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne et le chlorure d'aluminium.As a result, spectral studies have been undertaken to test this hypothesis and define the assumed interaction between 2-alkyl (4-methoxy-benzoyl) -3 benzofuran and aluminum chloride.
A titre d'exemple, on a obtenu les résultats suivants avec le chlorure d'aluminium et le n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.By way of example, the following results were obtained with aluminum chloride and n-butyl-2 (4-methoxy benzoyl) -3 benzofuran.
On a réalisé des solutions ternaires chlorure d'aluminium/n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne/benzène deutéré et on y a fait varier, de 0 à 3, le rapport molaire:
Ainsi, on a pu mettre en évidence:
- A. Par spectroscopie R.M.N. (résonnance magnétique nucléaire), l'absence de modification du groupement -OCH3 entre les rapports molaires 0 et 1 (8 = 3,2 ppm) et une augmentation de déplacement chimique de + 0,35 ppm entre les rapports 1 et 3 qui peut correspondre à une interaction éther-AICI3.
- B. Par spectroscopie I.R. (infra-rouge), l'absence pratiquement de modifications des absorptions caractéristiques des groupements C-O-C dans la zone 1200-1000 cm-1, dans le cas présent le groupement C-0-C du benzofuranne. Dans le toluène également par spectroscopie I.R. on a observé, pour des rapports molaires variant de 0 à 1,5 et lors de l'ajout de chlorure d'aluminium, la disparition de la bande v C = O "libre" à 1654 cm-1 du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne au profit d'une bande située à 1545 cm-1 (bande v C = 0 "associée").
- A. By NMR spectroscopy (nuclear magnetic resonance), the absence of modification of the -OCH 3 group between the molar ratios 0 and 1 (8 = 3.2 ppm) and an increase in chemical displacement of + 0.35 ppm between the ratios 1 and 3 which may correspond to an ether-AICI 3 interaction.
- B. By IR (infrared) spectroscopy, the practically absence of modifications of the absorptions characteristic of the COC groups in the area 1200-1000 cm -1 , in the present case the C-0-C group of benzofuran. In toluene also by IR spectroscopy, for molar ratios varying from 0 to 1.5, and during the addition of aluminum chloride, the disappearance of the "free" v C = O band at 1654 cm was observed. 1 of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran in favor of a band located at 1545 cm- 1 (band v C = 0 "associated").
L'abaissement de la fréquence de 100 cm-1 est l'indice d'une forte complexation. La disparition quasi totale de la bande libre pour le rapport molaire r = 1 montre que la totalité du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne est, à ce stade, engagé dans un complexe avec le chlorure d'aluminium et que ce dernier est probablement du type 1 : 1 sur le site cétone. Ce complexe moléculaire correspondrait donc à la formule:
Le complexe 1 : 1 ainsi défini a pu être isolé à partir de solutions chlorométhyléniques.The 1: 1 complex thus defined could be isolated from chloromethylenic solutions.
Il se présente sous la forme d'un solide jaune mal cristallisé. Maintenu à l'abri de l'humidité et à basse température (≤ 20° C), ce complexe apparaît stable. Il fond entre 25 et 40° C en se décomposant.It is in the form of a poorly crystallized yellow solid. Maintained away from humidity and at low temperature (≤ 20 ° C), this complex appears stable. It melts between 25 and 40 ° C while decomposing.
Le spectre I.R. du complexe moléculaire 1 : 1 en question, obtenu en opérant très rapidement pour éviter une hydrolyse (suspension dans une paraffine liquide) montre, par comparaison au spectre du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne en film, la disparition de la bande v C = O "libre". La bande v C = 0 "associée" apparaît large et mal définie entre 1500 et 1550 cm-1.The IR spectrum of the 1: 1 molecular complex in question, obtained by operating very quickly to avoid hydrolysis (suspension in a liquid paraffin) shows, by comparison with the spectrum of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran in film, the disappearance of the band v C = O "free". The band v C = 0 "associated" appears wide and ill-defined between 1500 and 1550 cm -1 .
Les spectres I.R. et R.M.N. du complexe 1 : 1 après dissolution dans le toluène ou le benzène montrent très exactement les perturbations spectrales observées lors de l'étude effectuée sur les solutions ternaires pour le rapport molaire r = 1 et dont les résultats sont rapportés précédemment.The spectra I.R. and R.M.N. of the 1: 1 complex after dissolution in toluene or benzene very precisely show the spectral disturbances observed during the study carried out on ternary solutions for the molar ratio r = 1 and the results of which are reported previously.
Les résultats des études spectrales des solutions ternaires ont également laissé supposer la formation d'un complexe moléculaire chlorure d'aluminium/n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans le rapport molaire 2 : 1. Cependant, le fait qu'il s'agisse d'un complexe 2 : 1 n'a pas été prouvé.The results of spectral studies of ternary solutions also suggested the formation of an aluminum chloride / n-butyl-2 (4-methoxybenzoyl) -3 benzofuran molecular complex in the 2: 1 molar ratio. However, the fact that it is a 2: 1 complex has not been proven.
Par contre, on a également pu mettre en évidence que des solutions toluéniques contenant le chlorure d'aluminium et le n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans le rapport r = 2 donnent naissance à un nouveau complexe par addition de ces solutions dans un hydrocarbure aromatique par exemple le benzène ou le toluène maintenu au reflux. Ce nouveau complexe correspondant à un complexe de déméthylation, répond à la formule:
Il se présente sous forme d'une poudre jaunâtre finement divisée fondant au delà de 300° C avec décomposition.It is in the form of a finely divided yellowish powder melting above 300 ° C with decomposition.
En conclusion, on peut affirmer qu'il y a interaction du groupement cétonique de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne avec le chlorure d'aluminium à basse température (≤ 20°C) dans un hydrocarbure aromatique tel que le benzène ou le toluène et ce, pour des rapports molaires chlorure d'aluminium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne allant jusqu'à 2, qu'il n'y a aucune interaction avec le groupement C-O-C benzofurannique et qu'une interaction faible apparaît avec le groupement éther uniquement au-delà du rapport 1.In conclusion, it can be affirmed that there is interaction of the keto grouping of 2-alkyl (4-methoxy benzoyl) -3 benzofuran with aluminum chloride at low temperature (≤ 20 ° C) in an aromatic hydrocarbon such than benzene or toluene and this, for aluminum chloride / 2-alkyl (4-methoxy-benzoyl) -3 benzofuran molar ratios of up to 2, that there is no interaction with the COC benzofuran group and that a weak interaction appears with the ether group only beyond the ratio 1.
On peut donc supposer que le complexe hypothétique chlorure d'aluminium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 2 : 1 qui se formerait à froid (température < 20°C) dans un hydrocarbure aromatique comme le benzène ou le toluène, se modifierait thermiquement avec migration d'une molécule de chlorure d'aluminium du groupement cétone vers le groupement éther de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne pour permettre la déméthylation.It can therefore be assumed that the hypothetical aluminum chloride / 2-alkyl (4-methoxy-benzoyl) -3 benzofuran 2: 1 complex which would form cold (temperature <20 ° C) in an aromatic hydrocarbon such as benzene or toluene , would thermally modify with migration of an aluminum chloride molecule from the ketone group to the ether group of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran to allow demethylation.
Un autre objet de l'invention se rapporte à un procédé de préparation des complexes moléculaires 1 : 1 de formule dans laquelle R, représente le radical
De même, l'invention se rapporte à un procédé de préparation des complexes moléculaires 2 : 1 de formule 1 dans laquelle R, représente le radical
Selon une mise en oeuvre préférée, on réalise à une température inférieure ou égale à la température ambiante, une solution de 1 à 2 moles de chlorure d'aluminium par mole d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans un hydrocarbure aromatique. On coule alors, dans un hydrocarbure aromatique porté au reflux, la solution ainsi obtenue qui contient le complexe chlorure d'aluminium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1 selon l'invention de manière à former le complexe chlorure d'aluminium/alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1 selon l'invention.According to a preferred implementation, a solution of 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3-benzofuran is produced at a temperature less than or equal to room temperature. aromatic hydrocarbon. Then poured into an aromatic hydrocarbon brought to reflux, the solution thus obtained which contains the aluminum chloride / alkyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex according to the invention so as to form the complex aluminum chloride / 2-alkyl (4-hydroxy benzoyl) -3 benzofuran 2: 1 according to the invention.
L'invention concerne également une solution contenant les complexes moléculaires de l'invention et convenant notamment comme milieu réactionnel pour provoquer la déméthylation du groupement éther d'un alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, solution formée au départ de 1 à 2 moles de chlorure d'aluminium par mole d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne et d'un hydrocarbure aromatique tel que le benzène ou le toluène comme solvant.The invention also relates to a solution containing the molecular complexes of the invention and particularly suitable as a reaction medium for causing the demethylation of the ether group of a 2-alkyl (4-methoxy-benzoyl) -3 benzofuran, solution formed from 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran and of an aromatic hydrocarbon such as benzene or toluene as solvent.
Cette solution, à température inférieure ou égale à la température ambiante, contient le complexe 1 : 1 selon l'invention et à la température de reflux, le complexe 2 : 1 de l'invention.This solution, at a temperature less than or equal to room temperature, contains the 1: 1 complex according to the invention and at reflux temperature, the 2: 1 complex of the invention.
Les alkyl-2 (méthoxy-4 benzoyl)-3 benzofurannes de départ sont des produits connus qui peuvent être préparés par exemple selon le procédé décrit dans Bull. Soc. Chim. France pp. 685-688 (1960) ou dans le brevet français No. 1 260 578, par condensation, selon la réaction de Friedel-Crafts, d'un alkyl-2 benzofuranne et du chlorure de méthoxy-4 benzoyle dans le benzène, à une température comprise entre 0°C et la température ambiante, et en présence de chlorure stannique comme catalyseur suivie d'hydrolyse en présence d'un acide fort tel que l'acide chlorhydrique.The starting alkyl-2 (4-methoxy benzoyl) -3 benzofurans are known products which can be prepared, for example, according to the process described in Bull. Soc. Chim. France pp. 685-688 (1960) or in French Patent No. 1,260,578, by condensation, according to the Friedel-Crafts reaction, of a 2-alkyl benzofuran and 4-methoxy-benzoyl chloride in benzene, at a temperature between 0 ° C and room temperature, and in the presence of stannic chloride as catalyst followed by hydrolysis in the presence of a strong acid such as hydrochloric acid.
Selon une méthode préférée, on prépare l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne à une température comprise entre -10°C et la température ambiante également selon la réaction de Friedel-Crafts à partir de l'alkyl-2 benzofuranne, d'un halogénure de méthoxy-4 benzoyle, de préférence le chlorure, d'un hydrocarbure aromatique comme solvant par exemple le benzène ou de préférence le toluène et en présence d'un catalyseur, avec hydrolyse ultérieure en présence d'un acide fort par exemple l'acide chlorhydrique. Dans cette variante, cependant on utilise comme catalyseur le chlorure ferrique.According to a preferred method, 2-alkyl (4-methoxy benzoyl) -3 benzofuran is prepared at a temperature between -10 ° C. and room temperature also according to the Friedel-Crafts reaction from 2-alkyl. benzofuran, of a 4-methoxy benzoyl halide, preferably chloride, of an aromatic hydrocarbon as solvent, for example benzene or preferably toluene and in the presence of a catalyst, with subsequent hydrolysis in the presence of an acid strong for example hydrochloric acid. In this variant, however, ferric chloride is used as catalyst.
On a pu remarquer, en effet, que ce composé conduit à des résultats supérieurs à ceux procurés par d'autres acides de Lewis tel que le chlorure d'aluminium, le chlorure de zinc, l'éthérate de trifluorure de bore ou le chlorure stannique. Par rapport à ce dernier, les avantages offerts par le chlorure ferrique peuvent se résumer comme suit:
- - chargement total du chlorure ferrique dans le réacteur, en une seule opération. Celle-ci se traduit par un gain de main d'oeuvre comparativement au procédé connu qui nécessite, en effet, plusieurs heures pour l'introduction du chlorure stannique
- - abaissement du prix de revient d'une part en raison de l'utilisation du chlorure ferrique au lieu du chlorure stannique, d'autre part en raison d'une réduction de 90 % de la quantité d'acide fort engagé pour l'hydrolyse
- - gain de rendement dû au fait que l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne peut être utilisé à l'état brut pour l'obtention des complexes moléculaires de l'invention
- - sécurité accrue pour le personnel en raison de l'utilisation du chlorure ferrique moins toxique que le chlorure stannique
- - réduction de la teneur en isomères d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne (produits d'acylation en positions 5 et 6 sur l'homocycle) avec accroissement du rendement. Par exemple, lors de la préparation du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne le procédé nécessitant l'emploi de chlorure stannique donne naissance à environ 5 % d'isomères alors que la méthode utilisant le chlorure ferrique ne procure qu'un maximum de 2 % de ces isomères. Un tel avantage est particulièrement intéressant car il évite la purification difficile des alkyl-2 (méthoxy-4 benzoyl)-3 benzofurannes sous forme huileuse.
- - total loading of ferric chloride in the reactor, in a single operation. This results in a saving in labor compared to the known process which requires, indeed, several hours for the introduction of stannic chloride
- - lowering of the cost price on the one hand due to the use of ferric chloride instead of stannic chloride, on the other hand due to a 90% reduction in the amount of strong acid used for hydrolysis
- - yield gain due to the fact that 2-alkyl (4-methoxy benzoyl) -3 benzofuran can be used in the raw state for obtaining the molecular complexes of the invention
- - increased safety for personnel due to the use of less toxic ferric chloride than stannic chloride
- - reduction in the content of isomers of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran (acylation products in positions 5 and 6 on the homocycle) with increased yield. For example, during the preparation of n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran the process requiring the use of stannic chloride gives rise to approximately 5% of isomers whereas the method using ferric chloride does not provide than a maximum of 2% of these isomers. Such an advantage is particularly interesting because it avoids the difficult purification of the alkyl-2 (4-methoxy-benzoyl) -3 benzofurans in oily form.
De manière surprenante, le chlorure ferrique se révèle, dans le cas présent, plus sélectif que le chlorure stannique tout en fournissant des rendements pratiquement quantitatifs.Surprisingly, ferric chloride appears, in the present case, more selective than stannic chloride while providing practically quantitative yields.
Les isomères du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dont il est question ci-dessus, ont été isolés et leur structure déterminée par spectrographie R.M.N. (résonnance magnétique nucléaire) du 13C.The isomers of n-butyl-2 (4-methoxybenzoyl) -3 benzofuran, mentioned above, were isolated and their structure determined by 13 C NMR (nuclear magnetic resonance) spectrography.
Il s'agit d'un mélange de n-butyl-2 (méthoxy-4 benzoyl)-6 benzofuranne et de n-butyl-2 (méthoxy-4 benzoyl)-5 benzofuranne dans des proportions approximatives 85 : 15.It is a mixture of n-butyl-2 (4-methoxy-benzoyl) -6 benzofuran and n-butyl-2 (4-methoxy-benzoyl) -5 benzofuran in approximately 85:15 proportions.
Ces impuretés, si elles ne sont pas éliminées, participent aux réactions ultérieures dans lesquelles le n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne est engagé et conduiront, par exemple, aux isomères correspondants du n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne d'abord puis aux isomères correspondants de l'amiodarone ensuite.These impurities, if they are not eliminated, participate in the subsequent reactions in which n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran is engaged and will lead, for example, to the corresponding isomers of n-butyl-2 (hydroxy -4 benzoyl) -3 benzofuran first then to the corresponding isomers of amiodarone then.
Les complexes moléculaires 2 : 1 de l'invention peuvent être utilisés en vue de la préparation des alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne.The 2: 1 molecular complexes of the invention can be used for the preparation of 2-alkyl (4-hydroxy-benzoyl) -3 benzofuran.
La solution de complexe moléculaire 2 : 1 de l'invention peut être constituée:
- - soit d'une solution extemporanée de complexe 2 : 1 en question dans le solvant choisi,
- - soit d'une solution de chlorure d'aluminium et d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans un rapport molaire 1 à 2 : 1 également dans le solvant choisi. Dans ce cas, la solution chlorure d'aluminium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne en question peut être préparée elle-même:
- - soit par introduction dans le solvant choisi de chlorure d'aluminium anhydre et d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne préalablement isolé de son milieu de préparation
- - soit par addition de chlorure d'aluminium anhydre dans une solution d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne brut c'est-à-dire non isolé de son milieu de préparation.
- - either of an extemporaneous solution of complex 2: 1 in question in the chosen solvent,
- - Or a solution of aluminum chloride and 2-alkyl (4-methoxy benzoyl) -3 benzofuran in a molar ratio 1 to 2: 1 also in the chosen solvent. In this case, the aluminum chloride / 2-alkyl (4-methoxy benzoyl) -3 benzofuran solution in question can be prepared itself:
- - Or by introduction into the chosen solvent of anhydrous aluminum chloride and 2-alkyl (4-methoxy benzoyl) -3 benzofuran previously isolated from its preparation medium
- - Or by addition of anhydrous aluminum chloride in a solution of 2-alkyl (4-methoxy benzoyl) -3 benzofuran crude, that is to say not isolated from its preparation medium.
Différents modes de mise en oeuvre des réactifs nécessaires à la préparation de la solution du complexe 2 : 1 selon l'invention et finalement à la réaction de déméthylation ont été testés à savoir:
- - chargement de l'ensemble des réactifs à température ambiante et chauffage jusqu'au reflux. Ce mode de réalisation, applicable au laboratoire, s'est révélé dangereux au niveau industriel suite au risque d'emballement de la réaction, soit en raison de l'exothermicité de celle-ci, soit en raison d'un départ trop violent du chlorure de méthyle formé,
- - introduction du chlorure d'aluminium dans l'hydrocarbure aromatique, chauffage jusqu'au reflux et coulée progressive, en maintenant le reflux, de la solution d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.
- - loading of all the reagents at room temperature and heating until reflux. This embodiment, applicable to the laboratory, has proved dangerous at the industrial level due to the risk of runaway reaction, either due to the exothermicity thereof, or due to an excessively violent departure of the chloride. of methyl formed,
- - introduction of aluminum chloride into the aromatic hydrocarbon, heating until reflux and progressive pouring, while maintaining the reflux, of the solution of 2-alkyl (4-methoxy benzoyl) -3 benzofuran.
Cette variante a pour inconvénient de maintenir, dans le milieu réactionnel, un très large excès de chlorure d'aluminium par rapport au dérivé de benzofuranne pendant toute la durée de la coulée, ce qui peut conduire à une désacylation partielle de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.This variant has the drawback of maintaining, in the reaction medium, a very large excess of aluminum chloride relative to the benzofuran derivative throughout the duration of the casting, which can lead to partial deacylation of the 2-alkyl. (4-methoxy benzoyl) -3 benzofuran.
Par contre, on a trouvé que la déméthylation en question peut être réalisée très aisément selon une mise en oeuvre tout à fait particulière.On the other hand, it has been found that the demethylation in question can be carried out very easily according to a completely particular implementation.
Ainsi, selon l'invention, on forme à une température inférieure ou égale à la température ambiante, une solution de 1 à 2 moles de chlorure d'aluminium par mole d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans l'hydrocarbure aromatique choisi, de manière à former le complexe chlorure d'alumimium/alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1 de l'invention et on coule la solution obtenue, par exemple une solution à 30 % environ de ce complexe dans le solvant en question maintenu au reflux, ce qui provoque la formation du complexe chlorure d'aluminium/alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1 de l'invention.Thus, according to the invention, a solution of 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran in l is formed at a temperature lower than or equal to room temperature. aromatic hydrocarbon chosen, so as to form the alumimium chloride / 2-alkyl (4-methoxy benzoyl) -3 benzofuran 1: 1 complex of the invention and the solution obtained is poured in, for example a solution at approximately 30% of this complex in the solvent in question maintained at reflux, which causes the formation of the aluminum chloride / 2-alkyl (4-hydroxy benzoyl) -3 benzofuran 2: 1 complex of the invention.
On réalise alors l'hydrolyse de la solution de complexe 2 : 1 ainsi formée comme indiqué précédemment c'est-à-dire en présence d'un acide fort à une température ne dépassant pas 75° C à 80° C.The hydrolysis of the 2: 1 complex solution thus formed is then carried out as indicated above, that is to say in the presence of a strong acid at a temperature not exceeding 75 ° C. to 80 ° C.
Selon une méthode connue pour réaliser la déméthylation du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, on chauffe ce composé à 210 - 220°C en présence de chlorhydrate de pyridine et on hydrolyse en présence d'acide chlorhydrique tel que décrit dans le brevet français No. 1 260 578.According to a known method for demethylating n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran, this compound is heated to 210-220 ° C in the presence of pyridine hydrochloride and hydrolyzed in the presence of hydrochloric acid such as described in French Patent No. 1,260,578.
Comparativement à cette méthode connue, la déméthylation de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, par l'intermédiaire des complexes moléculaires de l'invention présente plusieurs avantages parmi lesquels on peut citer:
- - une température de mise en oeuvre inférieure à celle du procédé connu. De ce fait, la synthèse peut être réalisée dans un appareillage classique permettant d'atteindre par exemple le reflux du toluène sous pression atmosphérique (110°C) ou sous pression réduite (80°C) tout en évitant l'emploi d'un thermofluide comme moyen de chauffage pour atteindre les conditions de température du procédé antérieur
- - l'élimination de l'emploi de pyridine toxique assurant de ce fait un gain de sécurité pour le personnel
- - un rendement et une qualité améliorés,
- - l'absence de l'impureté présente dans le procédé antérieur à raison de 3 à 10 % selon la teneur en eau du milieu réactionnel. Dans le cas de la déméthylation de l'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, cette impureté correspond à 1'(hydroxy-4 phényl)-2 propionyl-3 benzofuranne (P.F.: 171°C) et dans le cas du n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, il s'agit plutôt d'un produit de désacylation à savoir l'(hydroxy-4 phényl)-2 benzofuranne (P.F.: 196°C; spectre I.R.: absence de bande v C = 0, présence de bande OH; spectre R.M.N.: absence de n-C4H9).
- - a processing temperature lower than that of the known process. Therefore, the synthesis can be carried out in a conventional apparatus making it possible for example to reach the reflux of toluene under atmospheric pressure (110 ° C) or under reduced pressure (80 ° C) while avoiding the use of a thermofluid as a heating means to reach the temperature conditions of the previous process
- - the elimination of the use of toxic pyridine thus ensuring a safety gain for the personnel
- - improved yield and quality,
- - The absence of the impurity present in the previous process at a rate of 3 to 10% depending on the water content of the reaction medium. In the case of demethylation of 2-ethyl (4-methoxy-benzoyl) -3 benzofuran, this impurity corresponds to 1 '(4-hydroxyphenyl) -2-3-propionyl benzofuran (mp: 171 ° C.) and in the case of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran, it is rather a deacylation product, namely (4-hydroxyphenyl) -2 benzofuran (mp: 196 ° C; IR spectrum : absence of band v C = 0, presence of OH band; NMR spectrum: absence of nC 4 H 9 ).
La présence de telles impuretés est particulièrement gênante. En effet, celles-ci nécessitent au minimum une double purification de l'alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne sans possibilité de recyclage des eaux- mères. Ces impuretés étant généralement plus insolubles que l'alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne dans les solvants usuels, leur élimination s'avère particulièrement difficile.The presence of such impurities is particularly troublesome. Indeed, these require at least a double purification of the 2-alkyl (4-hydroxy-benzoyl) -3 benzofuran without the possibility of recycling the mother liquors. These impurities being generally more insoluble than 2-alkyl (4-hydroxy benzoyl) -3 benzofuran in the usual solvents, their elimination proves to be particularly difficult.
Il apparaît en conséquence que les alkyl-2 (hydroxy-4 benzoyl)-3 benzofurannes en question et notamment la benzarone, peuvent être obtenus avec grande facilité et nombreux avantages par l'intermédiaire des complexes moléculaires de l'invention.It therefore appears that the 2-alkyl (4-hydroxy-benzoyl) -3 benzofurans in question and in particular benzarone, can be obtained with great ease and numerous advantages via the molecular complexes of the invention.
Ces avantages sont particulièrement intéressants lorsque les alkyl-2 (méthoxy-4 benzoyl)-3 benzofurannes de départ sont préparés selon la méthode préférée de l'invention c'est-à-dire selon une réaction de Friedel-Crafts avec le chlorure ferrique comme catalyseur. En effet, il est possible de cette manière, de réaliser les différentes étapes de préparation c'est-à-dire la préparation de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne, la préparation des complexes moléculaires et la déméthylation, dans le même hydrocarbure aromatique, par exemple le toluène, en évitant ainsi l'isolement de l'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne intermédiaire. Ainsi, selon un autre de ses aspects, l'invention se rapporte à la préparation d'alkyl-2 (hydroxy-4 benzoyl)-3 benzofurannes par réaction entre:
- - un alkyl-2 benzofuranne et un halogénure de méthoxy-4 benzoyle, de préférence le chlorure, dans un hydrocarbure aromatique, par exemple le toluène, à une température comprise entre -10°C et la température ambiante et en présence de chlorure ferrique comme catalyseur puis hydrolyse en présence d'un acide fort, par exemple l'acide chlorhydrique, pour obtenir une solution d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne correspondant, procédé selon lequel:
- - on introduit, à température inférieure ou égale à la température ambiante, 1 à 2 moles de chlorure d'aluminium par mole d'alkyl-2 (méthoxy-4 benzoyl)-3 benzofuranne puis on coule, dans un hydrocarbure aromatique au reflux, par exemple le toluène, la solution ainsi formée,
- - on hydrolyse en présence d'un acide fort, par exemple l'acide chlorhydrique, à une température de l'ordre de 75 à 80°C, pour obtenir l'alkyl-2 (hydroxy-4 benzoyl)-3 benzofuranne désiré.
- a 2-alkyl benzofuran and a 4-methoxy-benzoyl halide, preferably chloride, in an aromatic hydrocarbon, for example toluene, at a temperature between -10 ° C. and room temperature and in the presence of ferric chloride as catalyst then hydrolysis in the presence of a strong acid, for example hydrochloric acid, to obtain a solution of corresponding alkyl-2 (4-methoxy-benzoyl) -3-benzofuran, process according to which:
- - 1 to 2 moles of aluminum chloride per mole of 2-alkyl (4-methoxy-benzoyl) -3 benzofuran are introduced at a temperature less than or equal to room temperature, then poured into an aromatic hydrocarbon at reflux, for example toluene, the solution thus formed,
- - Hydrolyzed in the presence of a strong acid, for example hydrochloric acid, at a temperature of the order of 75 to 80 ° C, to obtain the desired alkyl-2 (4-hydroxy-benzoyl) -3 benzofuran.
Les alkyl-2 (hydroxy-4 benzoyl)-3 benzofurannes peuvent être utilisés eux-mêmes comme intermédiaires de synthèse pour préparer notamment la benziodarone, la benzbromarone ou l'amiodarone selon des procédés connus.The 2-alkyl (4-hydroxy benzoyl) -3 benzofurans can themselves be used as synthesis intermediates to prepare in particular benziodarone, benzbromarone or amiodarone according to known methods.
Par exemple, la benziodarone et la benzbromarone peuvent être obtenues respectivement par iodation ou bromation de l'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne au moyen respectivement d'iode ou de brome en phase homogène et en présence d'une solution tampon acétate de métal alcalin/acide acétique et l'amiodarone peut être préparée par iodation du n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne, de manière analogue à celle décrite précédemment, pour obtenir le n-butyl-2 (diiodo-3,5 hydroxy-4 benzoyl)-3 benzofuranne suivie d'une éthérification par le chlorhydrate de diéthylamino-1 chloro-2 éthane en présence d'une solution tampon carbonate de métal alcalin/bicarbonare de métal alcalin.For example, benziodarone and benzbromarone can be obtained respectively by iodination or bromination of 2-ethyl (4-hydroxy-benzoyl) -3 benzofuran by means of iodine or bromine respectively in homogeneous phase and in the presence of a solution alkali metal acetate / acetic acid buffer and amiodarone can be prepared by iodination of n-butyl-2 (4-hydroxy benzoyl) -3 benzofuran, in a similar manner to that described above, to obtain n-butyl-2 ( 3,5-diiodo-4-hydroxy-benzoyl) -3 benzofuran followed by etherification with 1-diethylamino-2-chloroethane hydrochloride in the presence of an alkali metal carbonate / alkali metal bicarbonate buffer solution.
Les Exemples non limitatifs suivants illustrent l'invention:The following nonlimiting examples illustrate the invention:
On dissout 11,5 g (0,0373 mole) de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans 100 ml de chlorure de méthylène anhydre. On refroidit la solution à -10°C à l'abri de l'humidité et on y ajoute rapidement et en une fois 5 g (0,0373 mole) de chlorure d'aluminium anhydre. On filtre la solution totale pour éliminer les quelques impuretés en suspension et on évapore à sec sous pression réduite (p = 20 mm Hg; température < 10°C) et sous atmosphère d'azote séché sur ponce sulfurique.11.5 g (0.0373 mol) of n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran are dissolved in 100 ml of anhydrous methylene chloride. The solution is cooled to -10 ° C in the absence of moisture and is quickly added in one portion 5 g (0.0373 mole) of anhydrous aluminum chloride. The total solution is filtered to remove the few suspended impurities and evaporated to dryness under reduced pressure (p = 20 mm Hg; temperature <10 ° C) and under an atmosphere of dried nitrogen over sulfuric pumice.
Le miel obtenu ne cristallise pas au congélateur après 15 h à -20°C. On le reprend deux fois par 50 ml de tétrachlorure de carbone et on constate, la deuxième fois, une cristallisation après 48 h à -20° C.The honey obtained does not crystallize in the freezer after 3 p.m. at -20 ° C. It is taken up twice with 50 ml of carbon tetrachloride and a second crystallization is observed after 48 h at -20 ° C.
On isole et sèche les cristaux sous courant d'azote sec à -20°C et on les conserve au congélateur.The crystals are isolated and dried under a stream of dry nitrogen at -20 ° C. and they are stored in the freezer.
On obtient ainsi 14,8 g de complexe chlorure d'aluminium/n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1 sous la forme d'une masse cristalline jaune foncé, peu stable, s'hydrolysant rapidement.
- Rendement: 89,7 %
- P.F.:translucide à + 25°C
- entièrement fondu à + 40°C
- non réversible
- Yield: 89.7%
- PF: translucent at + 25 ° C
- fully melted at + 40 ° C
- not reversible
De la même manière que précédemment, on prépare le complexe chlorure d'aluminium/éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1.In the same manner as above, the aluminum chloride / ethyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex is prepared.
On dissout 30,8 g (0,1 mole) de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans 300 ml de toluène sec et on refroidit à -10°C à l'abri de l'humidité. On ajoute alors rapidement et en une fois 26,7 g (0,2 mole) de chlorure d'aluminium anhydre. On obtient ainsi une solution contenant le complexe chlorure d'aluminium/n- butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1, que l'on coule dans du toluène anhydre porté à la température de reflux. On maintient encore la température de reflux pendant une heure tout en distillant du toluène.30.8 g (0.1 mol) of n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran are dissolved in 300 ml of dry toluene and the mixture is cooled to -10 ° C in the absence of moisture. 26.7 g (0.2 mole) of anhydrous aluminum chloride are then added quickly and at once. A solution is thus obtained containing the aluminum chloride / n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex, which is poured into anhydrous toluene brought to reflux temperature. The reflux temperature is still maintained for one hour while distilling off toluene.
En fin de réaction, on refroidit progressivement le milieu réactionnel. La cristallisation s'amorce vers +40° C. On essore alors après 2 h de maintien à +5°C et on sèche le cake d'essorage en étuve à vide à +55°C sous courant d'azote sec.At the end of the reaction, the reaction medium is gradually cooled. The crystallization begins around + 40 ° C. It is then wrung after 2 hours of holding at + 5 ° C and the spin cake is dried in a vacuum oven at + 55 ° C under a stream of dry nitrogen.
On obtient ainsi 49 g de complexe chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1 sous forme d'une poudre jaûnatre finement divisée.
- P.F.: > 300°C avec décomposition
- Spectre LR.: absence de bande C = 0 libre, bande C = 0 associée
- Spectre R.M.N.: spectre très large, absence de signal -OCH3
- Dosage de l'aluminium (complexométrie): 9,36 - 9,5 - 9,6 % (théorie: 9,63 %).
- PF:> 300 ° C with decomposition
- LR spectrum: absence of free C = 0 band, associated C = 0 band
- NMR spectrum: very broad spectrum, absence of -OCH 3 signal
- Determination of aluminum (complexometry): 9.36 - 9.5 - 9.6% (theory: 9.63%).
De la même manière que précédemment, on prépare le complexe chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.In the same manner as above, the aluminum chloride / ethyl-2 (4-hydroxy-benzoyl) -3 benzofuran 2: 1 complex is prepared.
Dans un réacteur, on introduit 520 g (600 ml) de toluène et 174 g (1 mole) de n-butyl-2 benzofuranne. Sous agitation, on porte le mélange au reflux et on sèche le milieu et l'appareillage par étêtage au moyen d'un système Dean-Stark. On élimine ainsi par distillation environ 35 g (environ 40 ml) de toluène. On refroidit à température ambiante et on introduit rapidement en une fois, 174 g (1,02 mole) de chlorure de méthoxy-4 benzoyle. On glace à -10° ± 2°C et on introduit également rapidement et en une fois 130 g (0,8 mole) de chlorure ferrique anhydre.520 g (600 ml) of toluene and 174 g (1 mole) of 2-n-butyl benzofuran are introduced into a reactor. With stirring, the mixture is brought to reflux and the medium and the apparatus are dried by topping using a Dean-Stark system. About 35 g (about 40 ml) of toluene are thus distilled off. It is cooled to ambient temperature and rapidly introduced at once, 174 g (1.02 mole) of 4-methoxy benzoyl chloride. Ice is added to -10 ° ± 2 ° C and 130 g (0.8 mole) of anhydrous ferric chloride are also introduced quickly and in one go.
On maintient le milieu réactionnel à -10° ± 2°C pendant 15 min. puis on laisse revenir spontanément à température ambiante. On maintient pendant 6 heures sous agitation et on glace à nouveau vers 0°C. On introduit alors, progressivement 200 g d'eau épurée sans dépasser 20° C.The reaction medium is maintained at -10 ° ± 2 ° C for 15 min. then allowed to spontaneously return to room temperature. Maintained for 6 hours with stirring and ice again around 0 ° C. 200 g of purified water are then gradually introduced without exceeding 20 ° C.
On maintient 30 min. à température ambiante, on filtre l'insoluble (acide méthoxy-4 benzoïque) puis on rince sur le filtre avec 90 g de toluène. On réunit les filtrats dans l'ampoule, décante la phase aqueuse inférieure et lave la couche organique avec une solution de 30 g d'acide chlorhydrique à 36 % dans 200 g d'eau épurée puis avec de l'eau jusqu'à neutralité. On sèche la phase organique et on élimine le solvant sous vide jusqu'à une température de 80°C dans la masse sous pression résiduelle d'environ 50 mm Hg.We maintain 30 min. at room temperature, the insoluble material is filtered (4-methoxy benzoic acid) and then rinsed on the filter with 90 g of toluene. The filtrates are combined in the funnel, the lower aqueous phase is decanted and the organic layer is washed with a solution of 30 g of 36% hydrochloric acid in 200 g of purified water and then with water until neutral. The organic phase is dried and the solvent is removed in vacuo up to a temperature of 80 ° C. in the mass under residual pressure of approximately 50 mm Hg.
On obtient ainsi environ 308 g de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne sous forme brute.Approximately 308 g of n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran is thus obtained in crude form.
Rendement: environ 100 %Yield: about 100%
Le n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne obtenu selon cette méthode conduit en moyenne aux teneurs suivantes en impuretés connues par chromatographie sur couche mince.
Dans un réacteur muni de dispositifs d'introduction de réactifs, d'agitation et de réfrigération, on introduit 308,3 g (1 mole) de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne dans 625 g de toluène. Après refroidissement du mélange à 0°C, on ajoute, sous agitation rapide, 253,3 g (1,9 mole) de chlorure d'aluminium.In a reactor provided with devices for introducing reagents, stirring and refrigeration, the following are introduced 308.3 g (1 mole) of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran in 625 g of toluene. After cooling the mixture to 0 ° C., 253.3 g (1.9 mole) of aluminum chloride are added, with rapid stirring.
On obtient ainsi une solution contenant le complexe chlorure d'aluminium/n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1.This gives a solution containing the aluminum chloride / n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex.
Dans un second réacteur identique renfermant 493 g de toluène anhydre porté à la température de reflux, on introduit la solution toluénique contenant le complexe 1 : 1 ainsi préparée. On maintient le reflux du mélange réactionnel encore pendant une heure après la fin de l'addition tout en distillant du toluène (462 g), ce qui provoque la formation du complexe chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.In a second identical reactor containing 493 g of anhydrous toluene brought to reflux temperature, the toluene solution containing the 1: 1 complex thus prepared is introduced. The reflux of the reaction mixture is maintained for another hour after the end of the addition while distilling off toluene (462 g), which causes the formation of the aluminum chloride / n-butyl-2 (4-hydroxy-benzoyl) complex. ) -3 benzofuran 2: 1.
On obtient ainsi une solution toluénique de complexe moléculaire chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution of an aluminum chloride / n-butyl-2 (4-hydroxy-benzoyl) -3 benzofuran molecular complex is thus obtained, which is used as it is.
Dans un réacteur muni de dispositifs d'agitation, d'introduction de réactifs et d'un réfrigérant, on introduit 174 g (1 mole) de n-butyl-2 benzofuranne et 520 g de toluène. On entraine les traces d'eau par distillation azéotropique. On refroidit le mélange à 20°C et on ajoute rapidement 174 g (1,02 mole) de chlorure de méthoxy-4 benzoyle. Après refroidissement à -10°C, on traite le milieu par 130 g de chlorure ferrique ajoutés en une fois. Après 15 min. à cette température, on laisse le mélange revenir à la température ambiante et on l'y maintient pendant 6 h sous agitation. On hydrolyse par addition de 200 ml d'eau en ne laissant pas la température dépasser 20° C. Après 15 min. à cette température, on filtre un insoluble (acide méthoxy-4 benzoïque), on lave le filtre avec du toluène et on sépare la phase aqueuse. On lave la phase organique avec une solution de 30 g d'acide chlorhydrique à 36 % dans 200 ml d'eau ensuite avec de l'eau jusqu'à neutralité puis on sèche.174 g (1 mole) of 2-n-butyl benzofuran and 520 g of toluene are introduced into a reactor fitted with stirring devices, introduction of reagents and a condenser. Traces of water are caused by azeotropic distillation. The mixture is cooled to 20 ° C and rapidly added 174 g (1.02 mole) of 4-methoxy benzoyl chloride. After cooling to -10 ° C, the medium is treated with 130 g of ferric chloride added at once. After 15 min. at this temperature, the mixture is allowed to return to ambient temperature and is maintained there for 6 h with stirring. It is hydrolyzed by the addition of 200 ml of water while not allowing the temperature to exceed 20 ° C. After 15 min. at this temperature, an insoluble material (4-methoxy benzoic acid) is filtered, the filter is washed with toluene and the aqueous phase is separated. The organic phase is washed with a solution of 30 g of 36% hydrochloric acid in 200 ml of water then with water until neutral and then dried.
On obtiént ainsi une solution toluénique contenant environ 308 g (environ 100 %) de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution is thus obtained containing approximately 308 g (approximately 100%) of n-butyl-2 (4-methoxy benzoyl) -3 benzofuran which is used as it is.
Dans un réacteur, on introduit une solution toluénique de 308,3 g de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne brut (exprimé en extrait sec: 1 mole) telle qu'obtenue au paragraphe a) ci-dessus, c'est-à-dire une solution à environ 30 %.A toluene solution of 308.3 g of crude n-butyl-2 (4-methoxy-benzoyl) -3 benzofuran (expressed as dry extract: 1 mol) as obtained in paragraph a) above is introduced into a reactor. , that is to say a solution at about 30%.
Sous agitation, on ajoute rapidement en refroidissant à 0°C, 253,3 g (1,9 mole) de chlorure d'aluminium et on laisse revenir à température ambiante.With stirring, 253.3 g (1.9 mole) of aluminum chloride are added rapidly while cooling to 0 ° C. and the mixture is allowed to return to ambient temperature.
On obtient ainsi une solution toluénique contenant le complexe chlorure d'aluminium/n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1.A toluene solution is thus obtained containing the aluminum chloride / n-butyl-2 (4-methoxybenzoyl) -3 benzofuran 1: 1 complex.
Dans un second réacteur, on introduit 493 g de toluène, puis, sous agitation, on porte à reflux et on sèche l'appareillage et le solvant par azéotropie. En maintenant par chauffage le reflux du milieu, on ajoute en environ 2,5 ± 0,5 h la solution contenant le complexe 1 : 1 obtenue précédemment. On rince avec 138 g de toluène anhydre et on maintient 1 h à reflux franc tout en distillant du toluène (462 g) ce qui provoque la formation du complexe chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.493 g of toluene are introduced into a second reactor, then, with stirring, the mixture is brought to reflux and the apparatus and the solvent are dried by azeotropy. While maintaining the reflux of the medium by heating, the solution containing the 1: 1 complex obtained above is added in approximately 2.5 ± 0.5 h. Rinsed with 138 g of anhydrous toluene and maintained for 1 h at clear reflux while distilling off toluene (462 g) which causes the formation of the aluminum chloride / n-butyl-2 (4-hydroxy-benzoyl) -3 complex. benzofuran 2: 1.
On obtient ainsi une solution toluénique de complexe moléculaire chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution of an aluminum chloride / n-butyl-2 (4-hydroxy-benzoyl) -3 benzofuran molecular complex is thus obtained, which is used as it is.
Dans un réacteur, on introduit 146,2 g (1 mole) d'éthyl-2 benzofuranne (titre 99,8 %) et 520 g (600 ml) de toluène. Sous agitation, on porte le milieu au reflux et on sèche par étêtage au moyen d'un système Dean-Stark. On distille ainsi environ 35 g (environ 40 ml) de toluène. On refroidit à température ambiante et on ajoute rapidement en une fois 174 g (1,02 mole) de chlorure de méthoxy-4 benzoyle (titre 98 %). On glace à -10 ± 2°C et on introduit rapidement et en une fois 130 g (0,8 mole) de chlorure ferrique anhydre. On maintient le milieu réactionnel à cette température pendant 15 min. puis on laisse revenir spontanément à la température ambiante pendant 6 heures. On glace à 0°C et hydrolyse sans dépasser 10°C par ajout progressif de 200 g d'eau désionisée. On filtre l'insoluble (acide méthoxy-4 benzoîque) et on décante la phase aqueuse. On lave la phase organique avec une solution préalablement préparée, de 200 g d'eau désionisée et de 30 g d'acide chlorhydrique à 36 % puis à l'eau désionisée jusqu'à pH 5 à 6 de l'effluent. On distille environ 500 g de toluène sous pression réduite (température de la masse: 80°C, pression résiduelle: 80 à 100 mm Hg) puis on casse le vide à l'azote et on introduit 280 g de n-heptane. On cristallise à température ambiante, essore après 2h de glaçage à -5 à -10°C puis on sèche à poids constant en étuve ventilée à 50°C.146.2 g (1 mol) of 2-ethyl benzofuran (99.8% titre) and 520 g (600 ml) of toluene are introduced into a reactor. With stirring, the medium is brought to reflux and dried by topping using a Dean-Stark system. About 35 g (about 40 ml) of toluene are thus distilled. The mixture is cooled to ambient temperature and 174 g (1.02 mole) of 4-methoxy-benzoyl chloride (98% titre) are added quickly at once. Ice is added to -10 ± 2 ° C and 130 g (0.8 mole) of anhydrous ferric chloride are introduced quickly and at once. The reaction medium is maintained at this temperature for 15 min. then allowed to spontaneously return to room temperature for 6 hours. Ice at 0 ° C and hydrolysis without exceeding 10 ° C by gradual addition of 200 g of deionized water. The insoluble material (4-methoxy benzoic acid) is filtered and the aqueous phase is decanted. The organic phase is washed with a previously prepared solution of 200 g of deionized water and 30 g of acid hydrochloric acid at 36% then with deionized water until pH 5 to 6 of the effluent. About 500 g of toluene are distilled under reduced pressure (mass temperature: 80 ° C., residual pressure: 80 to 100 mm Hg), then the vacuum is broken with nitrogen and 280 g of n-heptane are introduced. It is crystallized at room temperature, wrung after 2 hours of icing at -5 to -10 ° C and then dried to constant weight in a ventilated oven at 50 ° C.
On obtient ainsi environ 260 g d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne brut.
- Rendement: environ 93 %
- P.F.: 81°C
- Yield: about 93%
- Mp: 81 ° C
Dans un premier réacteur, on introduit 280,3 g (1 mole) d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne cristallisé et 588 g de toluène. Sous agitation, on dissout par chauffage, sèche les réactifs par azéotropie et refroidit la solution obtenue à 10°C.280.3 g (1 mol) of ethyl 2 (4-methoxy-benzoyl) -3 crystallized benzofuran and 588 g of toluene are introduced into a first reactor. With stirring, it is dissolved by heating, the reagents are dried by azeotropy and the solution obtained is cooled to 10 ° C.
Dans un second réacteur parfaitement sec, on introduit 253 g de toluène anhydre puis, sous refroidissement, 241 g (1,8 mole) de chlorure d'aluminium anhydre. Om amène la température de masse à 0 ± 5°G et on ajoute la solution toluénique d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne préparée dans le premier réacteur. L'addition se fait en 90 min. environ sous refroidissement extérieur pour ne pas dépasser 15°C. On maintient alors à température inférieure ou égale à 15°C la solution contenant le complexe chlorure d'aluminium/éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1 ainsi formée.253 g of anhydrous toluene are introduced into a second perfectly dry reactor and then, under cooling, 241 g (1.8 mole) of anhydrous aluminum chloride. Om brings the mass temperature to 0 ± 5 ° G and the toluene solution of ethyl-2 (4-methoxy benzoyl) -3 benzofuran prepared in the first reactor is added. The addition is done in 90 min. approximately under external cooling so as not to exceed 15 ° C. The solution containing the aluminum chloride / ethyl-2 (4-methoxy-benzoyl) -3 benzofuran 1: 1 complex thus formed is then kept at a temperature less than or equal to 15 ° C.
Dans le premier réacteur, on introduit 356 g de toluène anhydre puis on place sous agitation et sous pression résiduelle de 300 - 350 mm Hg avant de porter le toluène au reflux (température de masse: 84 ± 1°C). On stabilise le vide et la température, on met l'installation en distillation puis on commence d'introduire régulièrement la solution du second réacteur contenant le complexe (temps total d'introduction du complexe: 4 à 5 h; distillation toluénique: environ 1400 g). On rince le second réacteur avec 48 g de toluène anhydre et on porte la masse à 100°C en réduisant progressivement la dépression dans le réacteur (distillation toluénique: environ 105 g) ce qui provoque la formation de complexe chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.356 g of anhydrous toluene are introduced into the first reactor and then the mixture is stirred and under a residual pressure of 300 - 350 mm Hg before bringing the toluene to reflux (mass temperature: 84 ± 1 ° C). The vacuum and the temperature are stabilized, the installation is distilled and then the solution of the second reactor containing the complex is introduced regularly (total time of introduction of the complex: 4 to 5 h; toluene distillation: approximately 1400 g ). The second reactor is rinsed with 48 g of anhydrous toluene and the mass is brought to 100 ° C. while gradually reducing the vacuum in the reactor (toluene distillation: approximately 105 g) which causes the formation of aluminum chloride / ethyl- complex. 2 (4-hydroxy benzoyl) -3 benzofuran 2: 1.
On obtient ainsi une solution toluénique de complexe moléculaire chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne.A toluene solution of aluminum chloride / ethyl-2 (4-hydroxy-4-benzoyl) -3-benzofuran molecular complex is thus obtained.
Dans un réacteur, on introduit 109,6 g (0,75 mole) d'éthyl-2 benzofuranne et 388 g de toluène. On sèche le milieu par azéotropie (distillat toluénique: environ 27 g). On refroidit à 20°C et on ajoute rapidement 130 g de chlorure de méthoxy-4 benzoyle. On refroidit à -10 ± 2°C et on ajoute rapidement 97 g de chlorure ferrique anhydre. On maintient durant 30 min. à basse température puis on laisse revenir à la température de 20 ± 3°C que l'on maintient durant 6 h. On hydrolyse par ajout de 150 g d'eau désionisée, on porte la masse à 40 ± 2°C et on décante la phase aqueuse. On lave la phase organique à 40 ± 2°C pendant 30 min. avec une solution, préalablement préparée, de 150 g d'eau désionisée et de 225 g d'acide chlorhydrique à 36 %. On décante et on lave toujours à 40°C, avec 3 à 5 fractions de 200 g d'eau désionisée jusqu'à pH > 5 de l'effluent. On traite la solution toluénique par 45 g de charbon actif. On porte au reflux et on élimine l'eau par azéotropie. On filtre à chaud pour éliminer les impuretés, rince toujours à chaud avec 68 g de toluène et réunit les filtrats.109.6 g (0.75 mole) of 2-ethyl benzofuran and 388 g of toluene are introduced into a reactor. The medium is dried by azeotropy (toluene distillate: approximately 27 g). Cool to 20 ° C and quickly add 130 g of 4-methoxy benzoyl chloride. Cool to -10 ± 2 ° C and quickly add 97 g of anhydrous ferric chloride. It is maintained for 30 min. at low temperature then allowed to return to the temperature of 20 ± 3 ° C which is maintained for 6 h. Hydrolysis is carried out by adding 150 g of deionized water, the mass is brought to 40 ± 2 ° C and the aqueous phase is decanted. The organic phase is washed at 40 ± 2 ° C for 30 min. with a solution, previously prepared, of 150 g of deionized water and 225 g of 36% hydrochloric acid. Decanted and always washed at 40 ° C, with 3 to 5 fractions of 200 g of deionized water until pH > 5 of the effluent. The toluene solution is treated with 45 g of activated carbon. The mixture is brought to reflux and the water is removed by azeotropy. It is filtered hot to remove impurities, always rinsed hot with 68 g of toluene and the filtrates are combined.
On obtient ainsi une solution toluénique contenant environ 190 g (environ: 90 %) d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution is thus obtained containing approximately 190 g (approximately: 90%) of ethyl-2 (4-methoxy benzoyl) -3 benzofuran which is used as it is.
Dans un premier réacteur parfaitement sec, on introduit une solution toluénique de 280,3 g d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne brut (exprimé en extrait sec - 1 mole) telle qu'obtenue au paragraphe a) précédent, c'est-à-dire une solution à environ 30 %. On refroidit à température inférieure ou égale à 5° C et, sous agitation, on ajoute rapidement et en une fois 266 g (2 moles) de chlorure d'aluminium anhydre pour former une solution contenant le complexe chlorure d'aluminium/éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne 1 : 1. On maintient cette solution contenant le complexe sous agitation durant 30 min. à température inférieure à 30°C et à l'abri de l'humidité.In a first perfectly dry reactor, a toluene solution of 280.3 g of ethyl-2 (4-methoxy-benzoyl) -3 benzofuran (expressed as dry extract - 1 mole) as introduced in paragraph a) is introduced. , that is to say a solution at about 30%. It is cooled to a temperature less than or equal to 5 ° C. and, with stirring, 266 g (2 moles) of anhydrous aluminum chloride are added quickly and at once to form a solution containing the aluminum chloride / ethyl-2 complex. (4-methoxy benzoyl) -3 benzofuran 1: 1. This solution containing the complex is kept under stirring for 30 min. at temperatures below 30 ° C and away from humidity.
Dans un second réacteur, on porte au reflux 348 g (400 ml) de toluène anhydre puis, sous reflux, on introduit en 1,5 à 2 h la solution toluénique contenant le complexe obtenue précédemment. Dès la fin d'introduction, on met l'appareil en distillation (distillat toluénique: environ 400 ml) et on place à nouveau sous reflux total durant 1 h, ce qui provoque la formation de complexe chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.In a second reactor, 348 g (400 ml) of anhydrous toluene are refluxed and then, under reflux, the toluene solution containing the complex obtained above is introduced over 1.5 to 2 hours. At the end of introduction, the apparatus is distilled (toluene distillate: approximately 400 ml) and again placed under total reflux for 1 h, which causes the formation of aluminum chloride / ethyl-2 complex ( 4-hydroxy benzoyl) -3 benzofuran 2: 1.
On obtient ainsi une solution toluénique de complexe moléculaire chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution of an aluminum chloride / ethyl-2 (4-hydroxy-4-benzoyl) -3-benzofuran molecular complex is thus obtained which is used as it is.
Dans un réacteur parfaitement sec, on introduit 244 g (280 ml) de toluène anhydre puis rapidement en une fois 266 g (2 moles) de chlorure d'aluminium anhydre. Sous agitation et en refroidissant pour ne pas dépasser 20°C, on ajoute progressivement une solution toluénique de 280,3 g d'éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne brut (exprimé en extrait sec = 1 mole) telle qu'obtenue à l'Exemple 6a) c'est-à-dire une solution à environ 30 %. On porte progressivement au reflux en 1 à 1,5 h puis on maintient 1 h à cette température.244 g (280 ml) of anhydrous toluene are introduced into a perfectly dry reactor, and then 266 g (2 moles) of anhydrous aluminum chloride are rapidly introduced at once. With stirring and cooling so as not to exceed 20 ° C., a toluene solution of 280.3 g of ethyl-2 (4-methoxy-benzoyl) -3 benzofuran is gradually added (expressed as dry extract = 1 mole) as 'obtained in Example 6a), that is to say a solution at about 30%. It is gradually brought to reflux in 1 to 1.5 h and then maintained for 1 h at this temperature.
On obtient ainsi une solution toluénique de complexe moléculaire chlorure d'aluminium/éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.There is thus obtained a toluene solution of aluminum chloride / ethyl-2 (4-hydroxy-benzoyl) -3 benzofuran 2: 1 molecular complex.
De la même manière que celle décrite précédemment mais à partir d'une solution toluénique de 308,3 g de n-butyl-2 (méthoxy-4 benzoyl)-3 benzofuranne (exprimé en extrait sec: 1 mole), on obtient une solution toluénique de complexe moléculaire chlorure d'aluminium/n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne 2 : 1.
- + + +
- + + +
Les Exemples suivants illustrent la préparation de dérivés de benzoyl-3 benzofuranne et notamment la benzarone, la benziodarone, la benzbromarone et l'amiodarone à partir des complexes moléculaires de formule 1 de l'invention.The following examples illustrate the preparation of 3-benzoyl-benzofuran derivatives and in particular benzarone, benziodarone, benzbromarone and amiodarone from the molecular complexes of formula 1 of the invention.
Dans une solution de 46,2 g d'acide chlorhydrique à 36 % dans 600 g d'eau, on verse, sous agitation, la solution toluénique de complexe moléculaire obtenue à l'Exemple 3b), refroidie vers 75°C. Après 15 min., on sépare le phase aqueuse et on lave la phase organique jusqu'à neutralité avec de l'eau. On sèche la phase toluénique par distillation azéotropique de l'eau (distillation de 92 g de toluène) et on la décolore par traitement à 800 C avec de la terre décolorante. Après filtration et rinçage du filtre avec du toluène, on refroidit le filtrat vers -5° à -10°C et on isole le produit désiré par essorage.In a solution of 46.2 g of 36% hydrochloric acid in 600 g of water, the toluene solution of molecular complex obtained in Example 3b) is poured, with stirring, cooled to 75 ° C. After 15 min, the aqueous phase is separated and the organic phase is washed until neutral with water. The toluene phase is dried by azeotropic distillation of water (distillation of 92 g of toluene) and it is discolored by treatment at 80 ° C. with bleaching earth. After filtration and rinsing of the filter with toluene, the filtrate is cooled to -5 ° to -10 ° C and the desired product is isolated by wringing.
On obtient ainsi 253 g de n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut.
- Rendement: 86 %
- P.F.:119°C
- Efficiency: 86%
- Mp: 119 ° C
Une chromatographie sur couche mince montre que ce composé est exempt d'(hydroxy-4 phényl)-2 benzofuranne.Thin layer chromatography shows that this compound is free of (4-hydroxyphenyl) -2 benzofuran.
A une solution de 108 g d'acide chlorhydrique à 36 % dans 530 g d'eau désionisée, on ajoute, en 1 à 2 h et sans dépasser 80°C, la solution toluénique de complexe moléculaire, obtenue à l'Exemple 5b), préalablement refroidie à 75°C. On décante la phase aqueuse inférieure à 75 - 80°C et on lave la couche organique à cette température avec 3 fractions chacune de 280 g d'eau désionisée. Après la dernière décantation, on sèche le milieu par azéotropie à pression normale par l'intermédiaire d'un système Dean-Stark jusqu'à obtention d'une température de tête de 108 - 110°C. On refroidit à 80°C et on traite durant 15 min. avec 11 g de terre décolorante. On filtre et rince à chaud avec 60 g de toluène. On réunit les filtrats, cristallise par refroidissement progressif et glace durant 2 h à -5°C avant d'essorer. On rince avec 2 fractions chacune de 120 g de toluène anhydre et glacé et on sèche à poids constant en étuve à vide à 50° C.To a solution of 108 g of 36% hydrochloric acid in 530 g of deionized water, the toluene solution of molecular complex, obtained in Example 5b), is added within 1 to 2 hours and without exceeding 80 ° C. , previously cooled to 75 ° C. The aqueous phase is decanted below 75-80 ° C and the organic layer is washed at this temperature with 3 fractions each of 280 g of deionized water. After the last decantation, the medium is dried by azeotropy at normal pressure via a Dean-Stark system until a head temperature of 108-110 ° C is obtained. Cool to 80 ° C and treat for 15 min. with 11 g of bleaching earth. It is filtered and rinsed with hot with 60 g of toluene. The filtrates are combined, crystallized by progressive cooling and ice-cold for 2 h at -5 ° C before drying. Rinsed with 2 fractions each of 120 g of anhydrous and iced toluene and dried to constant weight in a vacuum oven at 50 ° C.
On obtient ainsi environ 233 g d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut ou benzarone.Approximately 233 g of ethyl 2 (4-hydroxy benzoyl) -3 benzofuran or benzarone are thus obtained.
Rendement: 83 ± 3 % [par rapport à l'éthyl-2 (méthoxy-4 benzoyl]-3 benzofuranne).Yield: 83 ± 3% [relative to 2-ethyl (4-methoxy benzoyl] -3 benzofuran).
Sous agitation, on introduit dans 600 g d'eau désionisée, la solution toluénique de complexe moléculaire, obtenue à l'Exemple 6b), préalablement refroidie à 70 ± 5°C. On porte à nouveau rapidement au reflux puis on refroidit à 70 ± 5°C pour décanter la couche aqueuse inférieure. On lave la couche organique toujours à 70 + 5°C avec une solution de 42 g d'acide chlorhydrique à 36 % dans 266 g d'eau désionisée puis jusqu'à neutralité avec 4 fractions chacune de 266 g d'eau désionisée. On sèche la couche organique par azéotropie à pression normale (distillat toluène/eau: environ 244 g ou 280 ml) et on traite le milieu obtenu avec 84 g de terre décolorante pendant 15 min. à 80° C. On filtre, on rince à chaud avec 56 g (65 ml) de toluène et on réunit les filtrats. On cristallise par refroidissement et on essore après 2 h à -5 à -10°C. On rince avec 168 g (195 ml) de toluène glacé et on sèche à poids constant en étuve ventilée à 60°C.With stirring, the toluene solution of molecular complex, obtained in Example 6b), previously cooled to 70 ± 5 ° C, is introduced into 600 g of deionized water. The mixture is again brought to reflux quickly and then cooled to 70 ± 5 ° C. in order to decant the lower aqueous layer. The organic layer is always washed at 70 + 5 ° C. with a solution of 42 g of 36% hydrochloric acid in 266 g of deionized water and then until neutral with 4 fractions each of 266 g of deionized water. The organic layer is dried by azeotropy at normal pressure (toluene / water distillate: approximately 244 g or 280 ml) and the medium obtained is treated with 84 g of bleaching earth for 15 min. at 80 ° C. It is filtered, rinsed hot with 56 g (65 ml) of toluene and the filtrates are combined. Crystallized by cooling and filtered after 2 h at -5 to -10 ° C. Rinsed with 168 g (195 ml) of ice-cold toluene and dried to constant weight in a ventilated oven at 60 ° C.
On obtient ainsi environ 234 g d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut ou benzarone.Approximately 234 g of ethyl-2 (4-hydroxy benzoyl) -3 benzofuran or benzarone are thus obtained.
Rendement: environ 88 % [par rapport à l'extrait sec exprimé en éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne].Yield: approximately 88% [relative to the dry extract expressed as 2-ethyl (4-methoxy benzoyl) -3 benzofuran].
Sous agitation, on introduit dans 600 g d'eau désionisée la solution toluénique de complexe moléculaire, obtenue à l'Exemple 7, préalablement refroidie à 80 ± 5°C. On porte à nouveau rapidement au reflux, puis on refroidit à 70 ± 5°C pour decanter la couche aqueuse inférieure. On lave la couche organique toujours à 70 ± 5°C avec une solution de 42 g d'acide chlorhydrique à 36 % dans 266 g d'eau désionisée puis jusqu'à neutralité avec 4 fractions chacune de 266 g d'eau désionisée. On sèche la couche organique par azéotropie à pression normale (distillat toluène/eau: environ 244 g ou 280 ml) et on traite le milieu obtenu avec 84 g de terre décolorante pendant 15 min. à 80°C. On filtre, on rince à chaud avec 56 g (65 ml) de toluène et on réunit les filtrats. On cristallise par refroidissement et on essore après 2h à -5 à -10°C. On rince avec 168 g (195 ml) de toluène glacé et on sèche à poids constant en étuve ventilée à 60° C.With stirring, the toluene solution of molecular complex, obtained in Example 7, previously cooled to 80 ± 5 ° C. is introduced into 600 g of deionized water. The mixture is again brought to reflux quickly, then cooled to 70 ± 5 ° C. in order to decant the lower aqueous layer. The organic layer is always washed at 70 ± 5 ° C with a solution of 42 g of 36% hydrochloric acid in 266 g of deionized water and then until neutral with 4 fractions each of 266 g of deionized water. The organic layer is dried by azeotropy at normal pressure (toluene / water distillate: approximately 244 g or 280 ml) and the medium obtained is treated with 84 g of bleaching earth for 15 min. at 80 ° C. It is filtered, rinsed hot with 56 g (65 ml) of toluene and the filtrates are combined. Crystallized by cooling and filtered after 2 h at -5 to -10 ° C. Rinse with 168 g (195 ml) of ice-cold toluene and dry to constant weight in a ventilated oven at 60 ° C.
On obtient ainsi environ 266 g d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut ou benzarone.Approximately 266 g of ethyl 2-hydroxy-4-benzoyl-3 benzofuran or benzarone is thus obtained.
Rendement: 88 ± 1 % [par rapport à l'extrait sec exprimé en ethyl-2 (méthoxy-4 benzoyl)-3 benzofuranne].
- P.F.: 126°C.
- Mp: 126 ° C.
De la même manière que celle décrite précédemment mais au départ de la solution toluénique de complexe moléculaire obtenue à l'Exemple 8, on obtient environ 216 g d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut, ce qui représente un rendement de 81 ± 1 % par rapport à l'extrait sec exprimé en éthyl-2 (méthoxy-4 benzoyl)-3 benzofuranne.
- P.F.: 125° C.
- Mp: 125 ° C.
Sous agitation et à température inférieure ou égale à 75°C, on hydrolyse la solution toluénique de complexe moléculaire obtenue à l'Exemple 4b) par addition d'une solution de 46,2 g d'acide chlorhydrique à 36 % dans 600 g d'eau distillée. On rince l'appareillage avec 123 g de toluène que l'on ajoute ensuite au milieu d'hydrolyse. Après 15 min. à la température de 70°C dans la masse, on décante et on lave la couche organique, à 70°C avec des fractions de 308 g d'eau épurée jusqu'à neutralité. On sèche la couche organique par azéotropie tout en distillant environ 92 g de toluène.With stirring and at a temperature less than or equal to 75 ° C., the toluene solution of molecular complex obtained in Example 4b) is hydrolyzed by addition of a solution of 46.2 g of 36% hydrochloric acid in 600 g of 'distilled water. The apparatus is rinsed with 123 g of toluene which is then added to the hydrolysis medium. After 15 min. at the temperature of 70 ° C. in the bulk, the organic layer is decanted and washed, at 70 ° C. with fractions of 308 g of purified water until neutral. The organic layer is dried by azeotropy while distilling about 92 g of toluene.
On traite le milieu à 80°C avec 12,3 g de terre décolorante, filtre et rince avec 92 g de toluène chaud. On réunit les filtrats, refroidit à 35°C et attend que la cristallisation soit bien amorcée avant de glacer à -5 à -10°C. On maintient 2 h à cette température, essore, rince avec 200 g de toluène glacé et sèche à poids constant en étuve ventilée à 60° C.The medium is treated at 80 ° C. with 12.3 g of bleaching earth, filtered and rinsed with 92 g of hot toluene. The filtrates are combined, cooled to 35 ° C. and waits for crystallization to be well initiated before icing at -5 to -10 ° C. Maintained for 2 hours at this temperature, wring, rinse with 200 g of ice-cold toluene and dry to constant weight in a ventilated oven at 60 ° C.
On obtient ainsi environ 253 g de n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne brut.Approximately 253 g of crude n-butyl-2 (4-hydroxy-benzoyl) -3 benzofuran are thus obtained.
Rendement: environ 86 % (par rapport au n-butyl-2 benzofuranne).Yield: approximately 86% (relative to n-butyl-2 benzofuran).
Dans un réacteur de 41, on introduit 540 g de méthanol. Sous agitation, on ajoute alors successivement 300 g (2,4 moles) d'acétate de sodium trihydraté, 286 g d'iode et 424 g d'iode récupéré humide (2,3 moles au total). On amène le milieu réactionnel à 30 à 35°C et on introduit en une fois 294 g (1 mole) de n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne. On rince avec 60 g de méthanol et on porte le mélange au reflux en 30 à 45 min. (température dans la masse: 70 à 74°C). On arrête le chauffage et on introduit, en 10 min. environ, une solution préalablement préparée de 90 g (2,2 moles) d'hydroxyde de sodium en écailles dans 400 g d'eau épurée. L'exothermicité de la réaction maintient le reflux (76/77°C dans la masse) pendant le temps d'introduction. On maintient 2 h à reflux puis on modifie l'appareil en distillation à pression atmosphérique. On introduit, en 20 min. environ, une solution aqueuse de 320 g de bisulfite de sodium (35° B) et on poursuit la distillation jusqu'à atteindre 97 à 100°C dans la masse (température de tête: 87°C). On distille ainsi environ 800 ml (environ 680 g) de solvant. On refroidit au moyen d'un bain d'eau à 75 à 80°C et on introduit successivement et dans l'ordre 200 g d'eau épurée, 215 g d'acide chlorhydrique à 36 % et 1600 g de toluène. On porte au reflux pendant 10 min. (température de la masse: 84°C - dégagement d'anhydride sulfurique) et on décante la phase aqueuse inférieure. On lave la couche toluénique à 75 à 80°C successivement avec 400 g d'eau épurée, 100 g d'une solution aqueuse de bisulfite de sodium et 2 fractions chacune de 400 g d'eau épurée. On décante au maximum après le dernier lavage et on traite avec 22 g de charbon actif durant 30 min. au reflux. On filtre à chaud, on rince avec 380 g de toluène chaud et on réunit les filtrats.540 g of methanol are introduced into a reactor of 41. With stirring, 300 g (2.4 moles) of sodium acetate trihydrate, 286 g of iodine and 424 g of iodine recovered wet (2.3 moles in total) are then added successively. The reaction medium is brought to 30 to 35 ° C and 294 g (1 mole) of n-butyl-2 (4-hydroxybenzoyl) -3 benzofuran are introduced at once. Rinsed with 60 g of methanol and the mixture is brought to reflux in 30 to 45 min. (temperature in the mass: 70 to 74 ° C). The heating is stopped and introduced in 10 min. approximately, a previously prepared solution of 90 g (2.2 moles) of scaled sodium hydroxide in 400 g of purified water. The exothermicity of the reaction maintains reflux (76/77 ° C in the mass) during the introduction time. It is maintained for 2 hours at reflux and then the apparatus is modified by distillation at atmospheric pressure. We introduce, in 20 min. approximately, an aqueous solution of 320 g of sodium bisulfite (35 ° B) and the distillation is continued until reaching 97 to 100 ° C in the mass (head temperature: 87 ° C). About 800 ml (about 680 g) of solvent are thus distilled. Cooled by means of a water bath to 75 to 80 ° C and are introduced successively and in order 200 g of purified water, 215 g of 36% hydrochloric acid and 1600 g of toluene. The mixture is brought to reflux for 10 min. (mass temperature: 84 ° C - release of sulfuric anhydride) and the lower aqueous phase is decanted. The toluene layer is washed at 75 to 80 ° C successively with 400 g of purified water, 100 g of an aqueous solution of sodium bisulfite and 2 fractions each of 400 g of purified water. Decant as much as possible after the last wash and treat with 22 g of activated carbon for 30 min. at reflux. Filtered while hot, rinsed with 380 g of hot toluene and the filtrates are combined.
On obtient ainsi une solution toluénique de n-butyl-2 (diiodo-3,5 hydroxy-4 benzoyl)-3 benzofuranne que l'on utilise telle quelle.A toluene solution of 2-n-butyl-2 (3,5-diiodo-4-hydroxy-benzoyl) -3 benzofuran is thus obtained which is used as it is.
De la même manière que celle décrite précédemment mais à partir de 266,3 g (1 mole) d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne, on obtient l'éthyl-2 (diiodo-3,5 hydroxy-4 benzoyl)-3 benzofuranne ou benziodarone après élimination du toluène par distillation.In the same manner as that described above, but starting from 266.3 g (1 mole) of ethyl-2 (4-hydroxy benzoyl) -3 benzofuran, ethyl-2 (diiodo-3,5 hydroxy) is obtained. 4 benzoyl) -3 benzofuran or benziodarone after removal of toluene by distillation.
De même, à partir de 266,3 g (1 mole) d'éthyl-2 (hydroxy-4 benzoyl)-3 benzofuranne et de brome, on obtient l'éthyl-2 (dibromo-3,5 hydroxy-4 benzoyl)-3 benzofuranne ou benzbromarone après élimination du toluène par distillation.Similarly, from 266.3 g (1 mole) of ethyl-2 (4-hydroxy-benzoyl) -3 benzofuran and bromine, ethyl-2 (3,5-dibromo-4-hydroxy-benzoyl) is obtained. -3 benzofuran or benzbromarone after elimination of toluene by distillation.
Dans un réacteur, on introduit la solution toluénique de n-butyl-2 (diiodo-3,5 hydroxy-4 benzoyl)-3 benzofuranne obtenue au paragraphe b) ainsi que 800 g d'eau épurée et 177,3 g (1,03 mole) de chlorhydrate de diéthylamino-1 chloro-2 éthane. Sous agitation, on amène le milieu réactionnel à 40 ± 2°C et on l'y maintient durant 15 min. En contrôlant le départ d'anhydride carbonique, on introduit alors lentement en pluie 416 g (3 moles) de carbonate de potassium anhydre. On élève progressivement la température pour atteindre le reflux en 1 h. On maintient durant 3 h à cette température, on décante la couche aqueuse saline à 75 ± 5°C et on lave la couche toluénique, à cette température avec 4 fractions chacune de 800 g d'eau épurée. A la température de 60°C on traite la solution toluénique avec 20,5 g de charbon actif, on filtre, on rince avec environ 220 g de toluène et on réunit les filtrats.The toluene solution of n-butyl-2 (3,5-diiodo-3,5-hydroxy-benzoyl) -3 benzofuran obtained in paragraph b) is introduced into a reactor, together with 800 g of purified water and 177.3 g (1, 03 mol) of 1-diethylamino-2-chloroethane hydrochloride. With stirring, the reaction medium is brought to 40 ± 2 ° C and maintained there for 15 min. By controlling the departure of carbon dioxide, 416 g (3 moles) of anhydrous potassium carbonate are then slowly introduced in the rain. The temperature is gradually raised to reach reflux in 1 hour. Maintained for 3 h at this temperature, the aqueous saline layer is decanted at 75 ± 5 ° C and the toluene layer is washed, at this temperature with 4 fractions each of 800 g of purified water. At the temperature of 60 ° C., the toluene solution is treated with 20.5 g of activated carbon, filtered, rinsed with approximately 220 g of toluene and the filtrates are combined.
On obtient ainsi une solution toluénique de n-butyl-2 (diiodo-3,5 β-diéthylaminoéthoxy-4 benzoyl)-3 benzofuranne sous forme de base ou amiodarone.A toluene solution of n-butyl-2 (3,5-diiodo-3,5 β-diethylaminoethoxy-4 benzoyl) -3 benzofuran is thus obtained in the form of the base or amiodarone.
On amène à 60°C la solution de n-butyl-2 (diiodo-3,5 β-diéthylaminoéthoxy-4 benzoyl)-3 benzofuranne obtenue au paragraphe c) et on introduit en 45 min. 38,5 g de gaz chlorhydrique au moyen d'un tube plongeant. On laisse la température de la masse s'élever suite à l'exothermicité de la réaction sans toutefois dépasser 75° C.The solution of n-butyl-2 (3,5-diiodo-3,5 β-diethylaminoethoxy-4 benzoyl) -3 benzofuran obtained in paragraph c) is brought to 60 ° C. and introduced in 45 min. 38.5 g of hydrochloric gas using a dip tube. The temperature of the mass is allowed to rise following the exothermicity of the reaction without however exceeding 75 ° C.
On vérifie le pH franchement acide en fin d'introduction et après 30 min. de contact à 70 ± 5°C. On met progressivement sous vide de la trompe à eau et on distille environ 400 ml de toluène/eau/acide chlorhydrique (fin de distillation: pression résiduelle < 150 mm; température de la masse < 75°C). On cristallise sous agitation lente avec bain d'eau durant environ 8 heures et on essore à 10 à 15°C. On rince avec 4 fractions chacune de 180 ml de toluène filtré et on sèche jusqu'à poids constant en étuve ventilée à 60° C.The frankly acidic pH is checked at the end of introduction and after 30 min. contact at 70 ± 5 ° C. The water pump is gradually put under vacuum and about 400 ml of toluene / water / hydrochloric acid are distilled (end of distillation: residual pressure < 150 mm; mass temperature <75 ° C). It is crystallized with slow stirring with a water bath for about 8 hours and is filtered at 10 to 15 ° C. Rinsed with 4 fractions each of 180 ml of filtered toluene and dried to constant weight in a ventilated oven at 60 ° C.
On obtient ainsi environ 647,5g de chlorhydrate de n-butyl-2 (diiodo-3,5 β-diéthylaminoéthoxy-4 benzoyl)-3 benzofuranne ou chlorhydrate d'amiodarone.Approximately 647.5 g of n-butyl-2 hydrochloride (3,5-diiodo-3,5 β-diethylaminoethoxy-benzoyl) -3 benzofuran or amiodarone hydrochloride are thus obtained.
Rendement: environ 95 % [par rapport au n-butyl-2 (hydroxy-4 benzoyl)-3 benzofuranne].Yield: approximately 95% [relative to n-butyl-2 (4-hydroxy benzoyl) -3 benzofuran].
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT86870090T ATE40357T1 (en) | 1985-06-25 | 1986-06-23 | MOLECULAR COMPLEXES FORMED FROM A BENZOFURANE DERIVATIVE AND ALUMINUM CHLORIDE, THEIR PREPARATION AND USE. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8509669 | 1985-06-25 | ||
| FR8509669A FR2583754B1 (en) | 1985-06-25 | 1985-06-25 | MOLECULAR COMPLEXES FORMED FROM A BENZOFURAN DERIVATIVE AND ALUMINUM CHLORIDE, THEIR PREPARATION AND THEIR USE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0210156A1 EP0210156A1 (en) | 1987-01-28 |
| EP0210156B1 true EP0210156B1 (en) | 1989-01-25 |
Family
ID=9320657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP86870090A Expired EP0210156B1 (en) | 1985-06-25 | 1986-06-23 | Molecular complexes formed from a benzofurane derivative and aluminium chloride, their preparation and their use |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4766223A (en) |
| EP (1) | EP0210156B1 (en) |
| JP (1) | JPS62478A (en) |
| AT (1) | ATE40357T1 (en) |
| CA (1) | CA1305158C (en) |
| DE (1) | DE3661912D1 (en) |
| FR (1) | FR2583754B1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2653431B1 (en) * | 1989-10-23 | 1994-05-27 | Sanofi Sa | PROCESS FOR THE PREPARATION OF BENZOYL-3 BENZOFURAN DERIVATIVES. |
| US5118707A (en) * | 1990-10-31 | 1992-06-02 | The Procter & Gamble Company | Compositions for regulating skin wrinkles comprising a benzofuran derivative |
| US20030113330A1 (en) * | 1999-11-08 | 2003-06-19 | Uhal Bruce D. | Methods for treating pulmonary fibrosis |
| US6528955B1 (en) | 2000-03-30 | 2003-03-04 | Q2100, Inc. | Ballast system for a fluorescent lamp |
| CN103265513A (en) * | 2013-03-25 | 2013-08-28 | 德州学院 | Preparation method of 2-alkyl -3-(4-hydroxybenzene formyl) benzfuran |
| CN103242271A (en) * | 2013-04-11 | 2013-08-14 | 宜昌长江药业有限公司 | Process for preparing key intermediate 2-ethyl-3-p-hydroxybenzoyl-benzofuran of benzbromarone |
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
| CN106632180B (en) * | 2016-12-14 | 2019-04-02 | 成都摩尔生物医药有限公司 | The synthetic method of amiodarone impurity G and the application of amiodarone impurity G |
| CN108440469A (en) * | 2018-04-13 | 2018-08-24 | 宁波斯迈克制药有限公司 | A kind of method of industrialized production Benzarone |
| US20230218644A1 (en) | 2020-04-16 | 2023-07-13 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
| CN112442003B (en) * | 2020-12-17 | 2022-04-19 | 南京方生和医药科技有限公司 | Dronedarone intermediate impurity and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1260578A (en) * | 1956-12-21 | 1961-04-04 | Soc. Des Laboratoires Labaz | PROCESS FOR PREPARING SUBSTITUTED COUMARONES |
| NL284505A (en) * | 1961-11-24 | |||
| DE1493989A1 (en) * | 1964-07-09 | 1969-10-09 | Merck Ag E | UV light protection agents for technical or cosmetic purposes |
| US3331854A (en) * | 1964-12-14 | 1967-07-18 | American Cyanamid Co | Novel furan and thiophene compounds |
-
1985
- 1985-06-25 FR FR8509669A patent/FR2583754B1/en not_active Expired
-
1986
- 1986-06-11 JP JP61135875A patent/JPS62478A/en active Pending
- 1986-06-19 US US06/876,003 patent/US4766223A/en not_active Expired - Lifetime
- 1986-06-23 DE DE8686870090T patent/DE3661912D1/en not_active Expired
- 1986-06-23 AT AT86870090T patent/ATE40357T1/en not_active IP Right Cessation
- 1986-06-23 CA CA000512209A patent/CA1305158C/en not_active Expired - Fee Related
- 1986-06-23 EP EP86870090A patent/EP0210156B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1305158C (en) | 1992-07-14 |
| EP0210156A1 (en) | 1987-01-28 |
| JPS62478A (en) | 1987-01-06 |
| FR2583754A1 (en) | 1986-12-26 |
| FR2583754B1 (en) | 1987-10-23 |
| US4766223A (en) | 1988-08-23 |
| DE3661912D1 (en) | 1989-03-02 |
| ATE40357T1 (en) | 1989-02-15 |
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